cells

Review
The Role of Prostaglandins in Different Types of Cancer
Álvaro Jara-Gutiérrez and Victoriano Baladrón *

Área de Bioquímica y Biología Molecular, Departamento de Química Inorgánica, Orgánica y Bioquímica,

Facultad de Medicina de Albacete/CRIB/Unidad de Biomedicina, Universidad de Castilla-La Mancha/CSIC,
C/Almansa 14, 02008 Albacete, Spain; alvaro.jara@alu.uclm.es
* Correspondence: Victoriano.Baladron@uclm.es; Tel.: +34-967-599-200 (ext. 2926); Fax: +34-967-599-327

Abstract: The prostaglandins constitute a family of lipids of 20 carbon atoms that derive from polyunsatu-
rated fatty acids such as arachidonic acid. Traditionally, prostaglandins have been linked to inflammation,
female reproductive cycle, vasodilation, or bronchodilator/bronchoconstriction. Recent studies have high-
lighted the involvement of these lipids in cancer. In this review, existing information on the prostaglandins
associated with different types of cancer and the advances related to the potential use of them in neoplasm
therapies have been analyzed. We can conclude that the effect of prostaglandins depends on multiple
factors, such as the target tissue, their plasma concentration, and the prostaglandin subtype, among
others. Prostaglandin D2 (PGD2 ) seems to hinder tumor progression, while prostaglandin E2 (PGE2 )
and prostaglandin F2 alpha (PGF2α ) seem to provide greater tumor progression and aggressiveness.
However, more studies are needed to determine the role of prostaglandin I2 (PGI2 ) and prostaglandin J2
(PGJ2 ) in cancer due to the conflicting data obtained. On the other hand, the use of different NSAIDs
(non-steroidal anti-inflammatory drugs), especially those selective of COX-2 (cyclooxygenase 2), could
have a crucial role in the fight against different neoplasms, either as prophylaxis or as an adjuvant





 treatment. In addition, multiple targets, related to the action of prostaglandins on the intracellular
Citation: Jara-Gutiérrez, Á.;
signaling pathways that are involved in cancer, have been discovered. Thus, in depth research about the
Baladrón, V. The Role of prostaglandins involved in different cancer and the different targets modulated by them, as well as their
Prostaglandins in Different Types of role in the tumor microenvironment and the immune response, is necessary to obtain better therapeutic
Cancer. Cells 2021, 10, 1487. tools to fight cancer.
https://doi.org/10.3390/
cells10061487 Keywords: prostaglandin; COX-1; COX-2; NSAIDs; cancer

Academic Editors: Stephen Yarwood

and Tuula Kallunki

1. Introduction
Received: 11 May 2021
1.1. A Piece of History
Accepted: 9 June 2021
Published: 13 June 2021
In 1930, R. Kurzrok and C. C. Lieb demonstrated that the uterine endometrium
contracted and relaxed rhythmically after exposure to semen [1]. In 1939, Ulf von Euler
Publisher’s Note: MDPI stays neutral
stated that this contraction was due to the action of an unknown unsaturated lipid, which
with regard to jurisdictional claims in
he called prostaglandin [2]. Then, S. Bergstrom observed the effects of the administration
published maps and institutional affil- of prostaglandin E in humans [3]. Between 1962 and 1966, the team of S. Bergstrom and
iations. D. A. van Dorp reported having achieved the synthesis of PGE2 from arachidonic acid
and to have discovered the crystalline structure of PGF2α and PGE2 , which allowed the
synthesis of prostaglandins in sufficient quantities to carry out pharmacological studies [4].
In 1971, J. R. Vane demonstrated that ASA (acetyl salicylic acid, aspirin) and non-steroidal
anti-inflammatory agents inhibited the synthesis of prostaglandins [5]. For their research
Copyright: © 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
on prostaglandins, S. Bergstrom, B. Samuelsson, and R. Vane, received the Nobel Prize in
This article is an open access article
Medicine and Physiology in 1982.
distributed under the terms and
1.2. Structure of Prostaglandins
conditions of the Creative Commons
Attribution (CC BY) license (https:// Prostaglandins (PGs) are a family of lipids of 20 carbon atoms derived from polyun-
creativecommons.org/licenses/by/ saturated fatty acids, especially arachidonic acid (AA). Carbon atoms C8-C12 form a cy-
4.0/). clopentane ring, while carbons C1-C7 and C12-C20 constitute two parallel aliphatic chains

Cells 2021, 10, 1487. https://doi.org/10.3390/cells10061487 https://www.mdpi.com/journal/cells

Cells 2021, 10, 1487 2 of 33

(R1 and R2, respectively) [6,7]. PGs are not produced by specialized glands but by different
types of cells in the body, acting as autocrine and paracrine messengers. In addition, their
half-life is short. Along with thromboxanes, they are known as prostanoid lipids, and share
the same carbon skeleton. In turn, they are part of a larger group called eicosanoids, along
with leukotrienes, lipoxins and hydroeicosatheroid and epoxyeicosatrieneic acids [8].
Regarding the nomenclature of PGs, it is summarized as follows: the accompanying
letter to the acronym PG indicates the components of the cyclopentane ring and its solubility
in different solvents (A: unsaturated ketones, soluble in cold acetone; E: β-hydroxyketones,
soluble in ether; F: 1.3-dioles, soluble in phosphate buffer); the numeric subscript indicates
the number of double links present in parallel strings; and the symbolic subscript indicates
other structural details (α: OH group of C9 located on the same plane as the ring of R1;
β: OH group in a plane other than R1) [6,7,9].

1.3. Prostaglandin Synthesis

PGs derive from AA oxidation, a process catalyzed by enzymes called cyclooxyge-
nases (COX) or PGH (prostaglandin H) synthetases. In humans, there are two isoforms,
COX-1 and COX-2 [10–12]. Both share 60% of their amino acid sequence and have a similar
three-dimensional structure, although COX-1 and COX-2 are encoded by different chro-
mosomes (chromosomes 9 and 1, respectively) (2). COX enzymes are membrane proteins
with a molecular weight of approximately 70–74 kDa and possess four protein domains:
(1) amino-terminal signal peptide domain, which guides the protein to its destination in
the membranes. This domain has a longer length and greater hydrophobicity in the COX-1
isoform; (2) dimerization domain, which allows the stability of the protein by means of
disulfide bridges, which link it to the catalytic domain, and salt bridges; (3) membrane
binding domain, formed by four amphipathic helices that allow its insertion into the lipid
bilayer; (4) catalytic domain (carboxyl-terminal), which has two separate catalytic sites
with different functions (peroxidase and cyclooxygenase activities). Within this catalytic
domain, there is an arginine residue at position 120 (Arg120) essential for substrate binding
and inhibitory NSAIDs (non-steroidal anti-inflammatory drugs) action in COX-1, but it
does not seem to be as determinant in COX-2 [13–16].
The COX enzymes mature in the endoplasmic reticulum, and they are then transported
and inserted into the cell membrane, forming functional homodimers, with an access
channel that allows the entry of AA. Precisely, ASA acetylates a serine residue on the
surface of the access channel, irreversibly preventing the passage of the substrate, thus
stopping the chain of chemical reactions [17,18]. The COX-1 enzyme is constitutively
expressed in most tissues of the human body and is responsible for regulating the basal
homeostasis of prostanoid synthesis, whereas the COX-2 enzyme promotes the transient
and inducible synthesis of these compounds when eventual physiological or pathological
processes occur, responding to certain stimuli. Among these stimuli are interleukin 1 (IL1),
fibroblast growth factor (FGF), tumor necrosis factor (TNF), bacterial lipopolysaccharide
(LPS) and nuclear transcription factor NFκB [10]. However, basal expression of COX-2 has
been demonstrated in the brain, testis, tracheal epithelium and in the macula densa region
of the kidneys [10].
AA is a polyunsaturated acid consisting of 20 carbon atoms, found in the phospholipids
of the cell membrane. By the action of different extracellular stimuli (bradykinin, adrenaline,
thrombin, corticoids, among others), phospholipases A2 and C are activated in the first
phase of prostaglandin synthesis [19]. Phospholipase A2 directly releases AA from the phos-
pholipids phosphatidyl-choline and phosphatidyl-ethanolamine from the cell membrane.
Phospholipase C releases diacylglycerol (DAG) from phosphatidyl inositol, and from the
DAG generated, AA is released through the action of the enzyme diglyceride lipase. AA
then travels through the cytosol until it is metabolized by the cyclooxygenase pathway [20],
which generates prostaglandins and thromboxanes (TXA), by the lipoxygenase pathway,
generating leukotrienes (LTB) and lipoxins (LXA) [7], or by the cytochrome P450 pathway,
generating hydroeicosatrienoic acids (HETE) and epoxyeicosatrienoic acids (EET) [21].
Cells 2021, 10, 1487 3 of 33

Since the focus of this review is on PGs and the COX pathway, the remaining two
pathways of AA-derived products are briefly described below [22]. The lipoxygenase
(LOX) pathway gives rise to LTB and LXA. The enzymes required for LTB synthesis are
present in leukocytes, macrophages, and mast cells, while those required to form LXA
are found in leukocytes and platelets. Hyperactivity of this pathway has been associated
with rheumatoid arthritis, inflammatory bowel disease, allergic rhinitis, bronchial asthma,
osteoarthritis, and atherosclerosis. On the other hand, the cytochrome P450 pathway
allows obtaining the EETs thanks to the CYP2C (P450 arachidonic acid epoxygenase 2C)
and CYP2J (P450 arachidonic acid epoxygenase 2J) enzymes, and the HETEs by means of
the CYP4A (cytochrome P450 4A fatty acid omega hydroxylase) enzyme activity. From
EETs, dihydroxyeicosatrienoic acids (DHETEs) are generated by the action of the soluble
enzyme epoxide hydrolase (sEH). All these acidic compounds allow the maintenance of
vascular homeostasis by acting as vasodilators or vasoconstrictors depending on which
compound they are transformed into [8].
In the cyclooxygenase pathway, a series of reactions catalyzed by COX1/2 enzymes
culminate in the synthesis of the different types of PG and TXA. First, peroxidation leads
to prostaglandin G2 (PGG2 ), an unstable and short-lived product. Then, deperoxidation
generates prostaglandin H2 (PGH2 ), a direct precursor of other PGs (PGE2 , PGD2 , PGF2
and PGI2 ) and thromboxanes such as TXA2 , which are synthesized by different enzymes
depending on the tissue and the physiological state [7].

1.4. Mechanism of Action of Prostaglandins. Transport and Degradation

PGs cross the cell plasma membrane of cells into the extracellular medium by facil-
itated diffusion. PGs are anions at physiological pH, and as the intracellular voltage is
about 20 times more negative inside the cell than outside, the tendency is to exit to the
extracellular space. In addition, there is a concentration gradient of PGs; inside the cell
their concentration is higher than outside, thus favoring their outflow. The magnitude
of the effects of PGs depends not only on their synthesis, but also on their degradation,
preferentially in the lung. The elapsed time until they are catabolized is usually seconds,
preventing them from reaching the general circulation. Once they have fulfilled their func-
tion, PGs are carried into the cell by the prostaglandin transporter (PGT, SLCO2A1) [23].
Once inside, they are oxidized and inactivated by the enzyme 15-hydroxy-prostaglandin
dehydrogenase (15-PGDH). The final product is eliminated in the urine [24].
Most of the actions of prostanoids are mediated by receptors coupled to different G
(guanine nucleotide-binding protein) proteins that possess seven transmembrane domains
and are encoded by different genes. Each of the prostanoids has at least one different
receptor. Regarding PGs, eight different receptors have been described: two receptors for
PGD2 (DP1 and DP2), four for PGE2 (EP1, EP2, EP3 and EP4), one for PGF2α (FP) and one
for PGI2 (IP) [25]. The IP, DP1, EP2 and EP4 receptors mediate an increase in cAMP (cyclic
adenosine monophosphate) and have been termed “relaxant-type receptors”, whereas the
group composed of the FP and EP1 receptors associated with Gq (G protein heterotrimeric
that activates beta isoforms of phospholipase C) induce calcium mobilization and are
termed “contractor-type receptors”. In addition, FP receptors may be associated with RHO
(RAS homologous GTPase protein) protein bound to small Gs (G protein that stimulates the
cAMP-dependent pathway by activating adenylyl cyclase) protein via a Gq-independent
pathway [26]. The DP2 receptor belongs to a different subgroup and is considered a
member of the “chemoattractant receptors” subgroup. DP2 is associated with inhibitory
Gi (G protein that transmits an inhibitory signal from membrane receptors to adenylyl
cyclase) protein inhibiting cAMP synthesis and increasing intracellular Ca2+ concentration.
The EP3 receptor, formerly called “inhibitory receptor”, can bind to Gi or G12 (G protein
that link cell surface G protein-coupled receptors primarily to guanine nucleotide exchange
factors for the RHO small GTPases) and causes a decrease in intracellular cAMP levels,
increases Ca2+ concentration and activates the RHO protein associated with a family of
small G proteins [26].
Cells 2021, 10, 1487 4 of 33

1.5. General Functions of Prostaglandins

The prostaglandin functions depend on the organ or tissue, the receptor to which
they bind, and the physiological situation. Broadly speaking, these functions are shown
in Table 1. It could be concluded that they help to maintain homeostasis of the different
organs/tissues and that they compose an alert system to normal and pathological physio-
logical processes, giving rise to the appearance of inflammatory signs and pain, among
many others [27].

Table 1. Summary of prostaglandin (PG) general functions.

Biological System PG Mediator Physiological Effect
PGE2 , PGI2 Reduction of acid secretion; Increase of mucous secretion
Digestive system
Longitudinal smooth muscle contraction; Circulatory
PGE2
smooth muscle contraction
PGI2 , PGE2 Bronchodilator
Respiratory system
PGH2 , PGF2 α Bronchoconstriction
PGE2 , PGI2 Arterial vasodilation
Cardiovascular system
PGF2 α Inhibition of platelet adhesion and leukocyte aggregation
PGI2 , PGE2 Medullary blood flow, pressure diuresis
Renal system
PGI2 , PGE2 Renin release
PGE2 Natriuresis, diuresis
Inhibition of proliferation and activation of T and B
Immune system PGE2 , PGI2
lymphocytes
PGE2 Inflammation
Central nervous system
PGD2 , PGI2 Induction of sleep
Ovulation, implantation, endometrial contraction, and
Female reproductive system PGE2 , PGI2 , PGF2 α
synergism with oxytocin
Male reproductive system PGE1 , PGE2 , PGE3 , PGF2 α Fertility

1.6. Prostaglandin Inhibitors

There are different substances capable of preventing the formation of PGs by inhibiting
COX1/2 enzymes [28]. These substances interact with specific amino acids of the enzymes
to inhibit them. For example, ASA irreversibly binds to a serine-530 residue of the substrate
entry channel, preventing the entry of arachidonic acid into the active site of COX1/2
enzymes that result irreversibly inactivated, especially COX1 [29,30]. Other drugs, such
as ibuprofen and naloxen, act as competitive inhibitors of arachidonic acid and are more
specific of COX2 enzyme [30]. For its part, indomethacin produces a time-dependent inhibi-
tion of both isoforms thanks to the electrostatic interaction between its carboxyl group and
arginine-120 residue of the COX enzymes channel [31]. The presence of two valine amino
acids in COX-2 (isoleucine in COX-1) allows some inhibitors to act selectively on COX2,
thus avoiding the gastrointestinal and renal side effects typical of COX-1 inhibition [32].
Among the more selective COX-2 inhibitors, we find etoricoxib, lumaricoxib, nimesulide,
among others.

2. Cancer and Prostaglandins

Previously, it has been mentioned that PGs are involved in a wide variety of biological
processes. Within these processes, it is essential to include research on the involvement
of these compounds in the development of different types of neoplasms, which is the
objective of this review. We have revised many published works with interesting data
about prostaglandins that are involved in different types of cancer, and we have described
Cells 2021, 10, 1487 5 of 33

some of the latest therapeutic advances to treat cancer by acting on prostaglandins and
enzymes related to these neoplasms.

2.1. Prostaglandins in Skin and Bone Cancer

Skin cancer most often develops on skin exposed to the sun, but it can also occur
on areas of the skin not ordinarily exposed to sunlight. There are three major types of
skin cancer: basal cell carcinoma, squamous cell carcinoma, and melanoma, which have
different neoplastic characteristics, some of them related with prostaglandin actions.
In one study, a high expression of the enzyme aldo-keto reductase 1C3 (AKR1C3+ )
was found in skin squamous cell carcinoma, which reduces PGD2 levels by metabolizing
it to PGF2α . This same study showed that PGD2 inhibits the formation of new vessels and,
therefore, its reduction facilitates the neovascularization necessary for tumor progression [33].
Another study demonstrated that in this type of cancer, an increase in miR-31-5p
micro–RNA is needed, which generates a decrease in acyl-coenzyme A peroxisomal A
oxidase 1 (ACOX-1), an enzyme that favors normal concentrations of different lipids,
including PGs. Suppression of ACOX-1 is associated with elevated PGE2 concentrations
and increased tumor cell migration and invasion. In fact, it is proposed to use PGE2
concentrations in saliva as a biomarker of disease progression, since the higher the stage,
the higher the concentration of PGE2 in saliva [34].
The treatment of squamous cancer and other cancer with 15-deoxy-delta-12,14-prostaglandin
J2 (15d-PGJ2 ) has been shown to reduce cell growth, secondary to a lower concentration
of the oncogenic STAT3 (signal transducer and activator of transcription 3) factor [35].
Similarly, it has been described that at higher concentrations of prostacyclin (PGI2 ), the
5-year survival rate in this type of cancer is higher. The increase of this prostaglandin
would influence cell proliferation, cell migration and the inflammatory process [36].
A work carried out with mice showed that treatment of non-melanoma type cancer
with apigenin, a compound found in fruits and vegetables, inhibits its progression. This
substance produces inhibition of tissue polypeptide antigen (TPA), a tumor inducer driven
by exposure to ultraviolet B (UVB) radiation, and a reduction in the concentration of COX-2,
PGE1 , and EP1 and EP2 receptors [37]. Another study has also demonstrated the efficacy
of piroxicam as a preventive agent, as it also reduces COX-2 expression. Moreover, the
local use of piroxicam on actinic keratoses and field cancerization has also been reported,
confirming its efficacy as target therapy [38].
Elevated concentrations of PGF2α have also been found in melanoma tumor cells with
respect to healthy tissues [35]. In cell and mouse models, this prostaglandin interferes with
the mechanism of action of ASA. ASA blocks the expression of the sex-determining region
of the Y chromosome (SRY) related to high mobility group 2 (SOX2), thereby promoting
cell apoptosis. Increased PGF2α rescues such cells from cell death. Moreover, the use of
antagonists of this prostaglandin potentiates the action of ASA [39].
Melanotan II (MTII), a synthetic analogue of the alpha-melanocyte stimulating hor-
mone (alpha-MSH), potently inhibited the migration, invasion, and colony-forming ca-
pability of B16-F10 melanoma cells in vitro and in vivo despite a lack of influence on
proliferation [40]. MTII treatment inhibited COX-2 expression and PGE2 production via
PTEN (fosfatidilinositol-3,4,5-trisfosfato 3-fosfatasa) upregulation, thereby suppressing
melanoma progression. Hence, topical MTII therapy may facilitate a novel therapeutic
strategy against melanoma.
On the other hand, overexpression of staphylococcal nuclease domain containing 1
(SND1) has been found in several malignancies including osteosarcoma, which is the most
frequent primary bone tumor. Zhou and coworkers revealed that osteosarcoma tissues
from different patients expressed significantly high SND1 mRNA and protein expression
compared to normal bone tissues. They found that SND1 overexpression significantly
promoted cell proliferation and tumor growth in vitro cell lines and in vivo. Their results
also revealed that SND1 increased the production of PGE2 . The serum PGE2 level had a
significant positive association with the SND1 mRNA expression level in osteosarcoma
Cells 2021, 10, 1487 6 of 33

tissues. Additionally, they found that SND1 upregulated PGE2 expression through the
NFκB/cyclooxygenase2 (COX2) pathway. Targeting of SND1 as a new antitumor strategy
for patients with osteosarcoma and SND1 may also act as a potential biomarker of the
therapeutic strategies utilizing COX2 inhibitors [41].
Recent studies showed that the activation of prostaglandin receptor EP1 promotes cell mi-
gration and invasion in different types of cancer, including osteosarcoma. Niu and coworkers
investigated the role of EP1 in the proliferation of osteosarcoma cells in vitro and in vivo.
EP1 levels were significantly higher in osteosarcoma cells compared to osteoblasts. PGE2
or 17-PT-PGE2 (17-phenyl-trinor-prostaglandin E2) treatment increased the proliferation
and decreased the apoptosis of cells. Inhibition of EP1 by SC51089 or siRNA markedly
decreased the viability of cells. EP1 appears to be involved in PGE2 -induced prolifera-
tive activity of cells. Antagonizing EP1 may provide a novel therapeutic approach to the
treatment of osteosarcoma [42].

2.2. Prostaglandins in Breast Cancer

Breast cancer is a commonly reported cancer that is widely prevalent among women.
Its early detection improves patient survival and results in better outcomes. For diagnosis
and follow-up care, tumor markers are one of the feasible investigations to be ordered.
8-Iso-prostaglandin F2a (8-iso-PGF2α ) serves as a serum non-invasive marker reflecting
oxidative stress and subsequent damaging of DNA. The serum level of 8-iso-PGF2α in
the breast cancer patients (57.92 pg/mL) was significantly higher compared to those with
benign tumors (18.89 pg/mL) (p < 0.001) [43].
Currently, a preventive treatment for this type of cancer is tamoxifen, which is only
effective in cases of estrogen receptor (ER)-positive cells. A published review proposes
the use of NSAIDs as chemopreventive agents for this type of cancer due to their multiple
interactions with tumor development. NSAIDs inhibit tumor DNA synthesis, modu-
late ER concentration and the COX, NF-κB, caspases and WNT (wingless and Int-1)-β-
catenin-TCF4 (transcription factor 4) pathways, as well as glycogenesis, by inactivating
6-phosphofructose-1-kinase) [44].
The aldo-keto reductase (AKR) superfamily is gaining attention in cancer research.
AKRs are involved in important biochemical processes and have crucial roles in car-
cinogenesis and chemoresistance. The enzyme AKR1C3 has many functions, which in-
clude production of prostaglandins, androgens and estrogens, and metabolism of different
chemotherapeutics; AKR1C3 is thus implicated in the pathophysiology of different types
of cancer, including breast cancer. The actions of AKR1C3 can produce FP receptor ligands
whose activation results in carcinoma cell survival. 11β-Prostaglandin F2α, a bioactive
metabolite catalyzed by AKR1C3, stimulates prostaglandin F receptor, and induces slug
expression in breast cancer [45]. It has been demonstrated that a high concentration of the
PGF2α -bound FP receptor is significantly (p = 0.02) related to a higher level of Ki-67 (nuclear
protein related to cell proliferation) in AKR1C3+ breast cancer patients. Treatment of cells
with an AKR1C3 inhibitor reduces PGF2α levels comparable to those in healthy tissues.
With squamous skin cancer, a study found that high concentrations of PGI2 corresponded
with a reduction in survival time. Moreover, it has been determined that this prostaglandin
activates the ERK1/2-MAPK (extracellular signal-regulated kinase 1/2 mitogen-activated
protein kinase) and NF-κB pathways by binding to the FP receptor, leading to increased
resistance to chemotherapy treatment. This activation is slowed by using inhibitors of FP
(AL8810) and NF-κB (BAY 11e7082 and Parthenolide) [45].
As described above, a study described the activation of the AKT (protein kinase
B (PKB)-AP1 pathway in breast cancer by treatment with high concentrations of 15d-
PGJ2 . When this pathway is irregularly activated, it is normally modulated by the tumor
suppressor PTEN, which acts by dephosphorylating PIP3 (phosphatidylinositol (3,4,5)-
triphosphate). This study demonstrated that prostaglandin 15d-PGJ2 covalently interacts
with the cysteine-136 residue of PTEN and modifies it in such a way that it loses its ability
to inhibit the AKT-AP-1 pathway [46]. On the other hand, some authors have shown that
Cells 2021, 10, 1487 7 of 33

dihomo-γ-linoleic acid (DGLA) can act as an inhibitor of the COX-2 enzyme by inhibiting
the enzyme delta-5-desaturase, which converts DGLA into arachidonic acid. Once inhibited,
DGLA acts as a COX-2 substrate and is degraded to 8-hydroxyoctanonic acid that activates
the caspases and poly-ADP-ribose polymerase (PARP) pathways. In addition, inhibition
with DGLA has been shown to increase the efficacy of 5-fluorouracil treatment, which
decreases tumor migration and invasion [46].
A recent study has shown that the increased concentration of the PGE2 -EP2 com-
plex limits the expression of the membrane protein CD80 (cluster of differentiation 80) in
macrophages, which hinders macrophages polarization and the immune system (IS) re-
sponse to cancer in human and mouse cells. Knock-out mice of microsomal PG synthetase
1 (mPGES-1) eliminates this limitation [47]. On the other hand, an in vivo experiment with
different mouse models showed that ibuprofen reduces PGE2 levels and tumor volume in
a dose-dependent manner, associated with an increase in mature macrophages, increased
recruitment of CD45 (leukocyte common antigen)+ T lymphocytes, and decreased numbers
of immature monocytes [48].
The results of a case-control study with human breast cancer patients in a phase-II
randomized trial suggest that the perioperative use of β-antagonists such as propranolol,
and COX-2 inhibitors such as etodolac, can significantly block STAT and EGR3 (early
growth response protein 3) pathways, which would favor tumor dissemination. Regarding
cellular activity, an increase in NK (natural killer) lymphocytes and B cells associated with
a lower number of monocytes. Also, plasma interleukin 6 (IL-6) levels decreased [49].
In inflammation-associated carcinogenesis, COX-2 is markedly overexpressed, result-
ing in accumulation of various prostaglandins with oncogenic potential such as 15d-PGJ2 .
The epithelial-to-mesenchymal transition (EMT) is a process by which epithelial cells
lose their polarity and adhesiveness, and thereby gain migratory and invasive properties.
Treatment of human breast cancer MCF-7 cells with 15d-PGJ2 induced EMT as evidenced
by increased expression of Snail (zinc finger transcriptional repressor) and ZEB1 (zinc
finger E-box-binding homeobox 1), with concurrent down-regulation of E-cadherin and
production of CXCL8 (chemokine (C-X-C motif) ligand 8) as a putative activator of fibrob-
lasts, which may contribute to tumor-stroma interaction in inflammatory breast cancer
microenvironment [50].
On the other hand, it is known that the formation of new blood (angiogenesis) and
lymphatic (lymphangiogenesis) vessels are major events associated with most epithelial
malignancies, including breast cancer. Inflammation is a key mediator of angiogenesis and
lymphangiogenesis with aberrant expression of COX2, which is a major promoter of both
events by the activation of prostaglandin E receptor EP4 on tumor cells, and the induction of
oncogenic microRNAs. The COX-2/EP4 pathway also promotes additional events in breast
cancer progression, such as cancer cell migration, invasion, and the stimulation of stem-like
cells. EP4 antagonists hold a major promise in breast cancer therapy in combination with
other modalities including immune check-point inhibitors [51].

2.3. Prostaglandins in Lung Cancer

Lung cancer, also known as lung carcinoma, is a malignant lung tumor characterized
by uncontrolled cell growth in lung tissues. This growth can spread beyond the lung by
the process of metastasis into nearby tissue or other parts of the body. Most cancer that
starts in the lung, known as primary lung cancer, are carcinomas. The two main types are
small-cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (NSCLC).
Long-chain acyl-CoA synthetase (ACSL3) channels AA into phosphatidylinositol
to provide the lysophosphatidylinositol-acyltransferase 1 (LPIAT1) with a pool of AA
to sustain high prostaglandin synthesis. By using lung cancer cell lines, mouse models,
some authors show that the LPIAT1 knockdown suppresses proliferation and anchorage-
independent growth of non-small cell lung cancer by using cell lines and hinders in vivo
tumorigenesis. In primary patient-derived frozen lung adenocarcinoma samples, the
Cells 2021, 10, 1487 8 of 33

expression of LPIAT1 is elevated compared with healthy tissue and predicts poor patient
survival [52].
TNF-α (tumor necrosis factor alpha) has been confirmed to promote tumor growth
in laryngeal carcinoma. A work found a crosstalk between PGE2 and TNF-α signaling
pathways, and the interaction between GRK2 (G-protein-coupled receptor kinase 2) and
TRAF2 (TNF receptor associated factor 2), which leads to the activation of TNF-α–TRAF2-
MMP (cell matrix metalloprotease)-9 signaling, and results in the progression of laryngeal
carcinoma [53].
It has been shown both in lung and esophageal cancer cell lines and lung adenocar-
cinoma biopsy samples a link between activation of the CRTC1 (CREB-regulated tran-
scriptional coactivator 1) oncogene, inactivation of the tumor suppressor LKB1 (hepatic
kinase B1), and the presence of glycosylated COX-2 in pulmonary adenocarcinoma. CRTC1
potentiates the cAMP/CREB (transcription factor that binds to DNA sequences “cAMP
response elements”) intracellular signaling pathway, which promotes tumor development.
By using COX-2 inhibitors such as niflumic acid (NS-398), tumor growth was reduced in
CRTC1+ /LKB1− cases. The glycosylated COX-2-synthesized prostaglandin PGE2 binds to
the EP2 y EP4 receptors and causes dephosphorylation of CRTC1, which in turn leads to
increased COX-2 activation [54].
Other authors have found that high levels of the microRNA miR-574-5p are related
to elevated concentrations of the prostaglandin PGE2 .both in lung adenocarcinoma cell
line and lung non-tumor and tumor tissue samples. This microRNA acts as an inhibitory
substrate of the ARN1-binding protein in the CUG triplet repeat (CUGBP1), which under
physiological conditions suppresses PEGS-1 (PG synthetase 1). Furthermore, the upregula-
tion of this microRNA is associated with high serum levels of interleukin 1β (IL-1β), typical
in cases of non-small cell lung cancer with poor prognosis. The use of PGES-1 inhibitors
abrogates the effect of miR-574-5p [55].
On the other hand, it has been shown that treatment of human non-small cell lung
cancer cells with prostaglandins 15d-PGJ2 and PGD2 results in increased apoptosis due
to increased ROS (reactive oxygen species) synthesis and activation of the caspases path-
way [34]. Also, overexpression of the enzyme prostacyclin synthetase (PGIS) in lung cancer
cell lines and mouse models has been shown to inhibit MHC-II (major histocompatibility
complex-II)+ lung cancer growth, independently of PGI2 , through recruitment of T-CD4
(cluster of differentiation 4)+ lymphocytes [56].
A randomized clinical trial with 5888 patients demonstrated that the use of NSAIDs
leads to a reduction in lung tumor mass and fewer metastases [57]. Also, a retrospective
case-control analysis to determine the effect of NSAID use on the incidence of lung cancer
identified 1038 patients with lung cancer from a review of pathology data at several large
hospital centers. The study suggested that smokers who regularly use NSAIDs might
benefit from a possible protective effect against lung cancer [58].

2.4. Prostaglandins in Liver Cancer

There is a well-known relationship between the appearance of hepatocarcinoma and
the proliferation of stellate cells. Stellate cells produce a dysregulation of the immune
system, generating a decrease in regulatory T lymphocytes and an increase in myeloid-
derived suppressor cells (MDSC), which favors tumor progression.
One study performed with cell lines and mouse models confirmed that the increase
in stellate cells is due to increased activation of the COX2-PGE2 -EP4 pathway in these
cells [59]. These authors used COX-2 inhibitors such as SC-236 to inhibit the accumulation
of stellate cells and stop the spread of liver cancer. The use of EP4 inhibitors, such as
AH23848 was also effective, but only in in vitro tests.
Another study showed that prostaglandin PGE2 increases MYC (myelocytomatosis
and tumor transcription factor) oncogene concentration by activating the EP4-protein-G-
Adenylate cyclase-cAMP-kinase A-CREB pathway. This increase is not sufficient to trigger
the onset of cancer, but it does facilitate its spread [60].
Cells 2021, 10, 1487 9 of 33

2,5-Dimethylcelecoxib (DMC) is a targeted inhibitor of mPGES-1, a key enzyme in the

PGE2 synthesis pathway of inflammatory mediators and the inhibition of growth of hepati-
tis B virus (HBV)-related hepatocellular carcinoma (HCC). DMC promotes HBV-related
HCC immune microenvironment, which not only enrich the relationship between inflam-
matory factors (mPGES-1/PGE2 pathway) and the immunosuppression programmed
death-ligand 1 (PD-L1), but also provide an important strategic reference for multitarget
or combined immunotherapy of HBV-related HCC. By using mouse models and human
tissue samples, these authors demonstrated that DMC combined with atezolizumab had
more significant antitumor effect and stronger blocking effect on PD-L1 pathway [61].

2.5. Prostaglandins in Digestive System and Pancreas Cancer

Digestive cancer can develop along the entire digestive tract (esophagus, stomach, small
intestine, large intestine, anus) as well as in other organs, such as the liver, pancreas, and biliary
tracts. Among them, the number of colorectal cancer patients is increasing worldwide.
In a study based on human patients with esophageal squamous cancer, an elevated
level of a subtype of Zinc transporter ZIP5 was observed. Inhibition of ZIP5 reduces
metastasis and levels of cyclin D1 and COX-2 [62]. Host immunity plays a vital role in
tumorigenesis, including tumor invasion and metastasis. The enzyme 15-PGDH, which
plays a key role in prostaglandin degradation, is a critical inflammatory mediator in
gastric cancer tumorigenesis. A study with gastric carcinoma patients demonstrated
that 15-PGDH may contribute to anti-tumor immunity by regulating FOXP3 (fork head
box protein 3) [63]. Also, a study with 277 patients showed that the presence of the
prostaglandin PGD2 reduces tumor expansion of gastric adenocarcinoma by inhibiting the
peroxisome proliferator-activated receptor gamma (PPARγ) pathway [36]. An interesting
study proposes a connection between Helicobacter pylori infection and the development
of gastric adenocarcinoma. Infection triggers an increase in COX-2 concentration, which
favors the onset of tumor expansion. Prophylaxis based on the use of NSAIDs has been
shown to be effective, considering the risk of gastro- and cardiotoxicity. In addition, it has
been confirmed that the use of selective cyclooxygenase type 2 inhibitors (COXIB) can stop
this gastric adenocarcinoma growth [62].
COX-2, activated in response to inflammatory stimuli, is also one of the major
molecules that is involved in the development and progression of colorectal cancer. It has
been shown that COX-2 inhibitors prevent the carcinogenesis and help in the treatment of
sporadic or familial cases as shown by an overall increase in the survival rate. However,
prolonged use of these inhibitors is associated with an increase in the risk of development
of cardiovascular complications [64]. One study performed with cell lines, human tissues
and mouse models showed that upregulation of the co-activator CRTC1 stimulates expres-
sion of the COX-2 gene and the production of prostaglandin PGE2 , which in turn leads
to dephosphorylation and activation of CRTC1, closing the feedback loop that increases
tumorigenicity of colorectal cancer [65]. Another study performed in cell lines proposes
that the XRCC5 (X-ray repair cross complementing 5) protein, involved in DNA repair
and telomere maintenance, and the transcription factor p300, which phosphorylates the
XRCC5 gene, potentiate COX-2 expression. XRCC5/p300/COX-2 pathway could be a new
therapeutic target since the use of p300 inhibitors seems to reduce COX-2 expression [66].
Several case-control and cohort studies demonstrate that continued prevention with
ASA reduces the incidence of adenomas and mortality from this colorectal cancer. The ef-
fects of ASA begin to be significant after 3 years from the start of the treatment and with
doses between 75 and 325 mg/day, with a greater impact on the proximal region of the
colon [67]. A randomized clinical trial with 14,743 patients demonstrated that the use of
NSAIDs achieves a reduction in tumor mass and a lower number of metastases in this type
of cancer [57]. Similarly, another study with stage III patients treated with ASA resulted
in a decrease in mortality and neoplastic recurrence of colorectal cancer [62]. In addition,
patients receiving combined treatment with ASA and statins were found to have lower
levels of PG compared to those receiving only one of the treatments [68]. Another study
Cells 2021, 10, 1487 10 of 33

with mouse models suggests that the use of sulindac in 15-PGDH knockouts could be
a better alternative to other NSAIDs, since it reduces the number of new adenomas in
the colon, although it is associated with greater inflammatory lesions in the proximal
colon. Also, the knock-out of 15-PGDH has been associated with increased resistance to
aspirin and celecoxib [69]. Finally, the treatment of colorectal cancer tumor cells with IP6
(inositol hexaphosphate) decreases COX-2 mRNA expression and activates genes of the
lipoxygenase pathway, which reduced the concentration of PGE2 [70].
On the other hand, a study in different cell lines demonstrated that treatment with
inhibitors of the PGE2 -EP4 complex reduces the formation of new adenoma-like prema-
lignant lesions in the colon, with reduced activation of the PI3K (phosphatidylinositol
3-kinase)-AKT-mTOR (muscular target of rapamycin) and ERK1/2-MAPK signal transduc-
tion pathways [71]. The prostaglandin PGF2α has been shown to increase the migration and
invasiveness of colorectal tumor cells [45]. However, the treatment of cells with 15d-PGJ2
results in the inhibition of telomerase, through modulation of the MYC oncogene, which
directs these cells to a state of senescence or cell death [35]. A genetic study with cell lines
and immunodeficient mice showed that tumor progression in colorectal cancer is related
to the overexpression of the enzyme prostaglandin synthase E, due to an increase in the
EGR1 (early growth response protein 1) factor, produced by the action of prostaglandin
PGF2β . When a PGF2β receptor antagonist was used, EGR1 and PGE2 concentrations were
reduced [72]. It has been also proposed that the urinary PG urinary metabolite (PGM) may
be an early diagnostic marker of colon cancer, since its levels are higher in patients already
diagnosed with this pathology, followed by patients with multiple adenomas [73].
Accumulating evidence has shown that the tumor microenvironment, including
macrophages, neutrophils, and fibroblasts, plays an important role in the development
and progression of colorectal cancer. Although targeting the TME could be a promising
therapeutic approach, the mechanisms by which inflammatory cells promote colorectal
cancer tumorigenesis are not well understood. Therapies targeting the specific downstream
molecules of PGE2 signaling could be a promising approach [74].
As commented above for colon cancer, a study in different cell lines, including hu-
man pancreatic carcinoma cell line PANC-1, demonstrated that prostaglandin E2 activates
the mTORC1 pathway through an EP4/cAMP/PKA- and EP1/Ca2+ -mediated mecha-
nism [71]. The pancreatic tumor stroma is composed of phenotypically heterogeneous
cancer-associated fibroblasts with both pro- and anti-tumorigenic functions. Calcipotriol
decreased cancer-associated fibroblasts proliferation and migration and reduced the release
of the pro-tumorigenic factors such as prostaglandin E2 in cancer-associated fibroblasts
(CAFs) isolated from human pancreatic tumor tissues. However, calcipotriol promoted
PD-L1 upregulation, which could influence T cell mediated tumor immune surveillance
and T cell activation [75]. Vitamin D3 analogues appear to have dual functions in the
context of pancreatic cancer, which could have important clinical implications.
Several studies have shown that pancreatic cells do not express COX-1, which explains
why ASA does not adequately prevent disease progression. Therefore, selective COX-2
inhibitors, such as COXIB-2 (celecoxib), should be used to reduce elevated COX-2 activity.
However, COXIB-2 inhibitors have not demonstrated comparable efficacy to cisplatin and
gemcitabine as a treatment for this type of cancer [62].

2.6. Prostaglandins in Renal and Urinary Cancer

Almost all kidney cancers are renal cell carcinomas. Most solid kidney tumors are
cancerous, but purely fluid-filled tumors (cysts) generally are not. Exposure to cadmium
(Cd) is considered to be a threat to human health. The kidney is the main target of Cd
accumulation, which increases the risk of renal cell carcinoma. Shi and coworkers suggested
that cells exposed to low dose Cd promoted migration of renal cancer cells, which was
not dependent on Cd-induced reactive oxygen species (ROS) and intracellular Ca2+ levels.
Cd exposure induced cAMP/PKA-II (protein kinase A type 2)-COX2, which mediated
cell migration and invasion, and decreased expressions of the EMT marker, E-cadherin,
Cells 2021, 10, 1487 11 of 33

but increased expressions of N-cadherin and Vimentin. This study might contribute to
understanding of the mechanism of Cd-induce progression of renal cancer and future studies
on the prevention and therapy of renal cell carcinomas [76]. It has also been shown that the
higher the expression of COX-1, the higher the degree of malignancy of the renal tumor [36].
The use of 15d-PGJ2 in patients undergoing radical nephrectomy for renal cell carci-
noma caused apoptosis of tumor cells through the caspases pathway and the activation of
JNK (c-Jun N-terminal kinase) and AKT kinases, associated with an increase in intracellular
calcium, and independently of the activation of the PPARγ pathway [35]. In another study
with 20 patient samples, higher PGE2 levels were observed in renal carcinoma samples
compared with non-neoplastic renal parenchyma. However, these levels were not related
to tumor size, Fuhrman grade, TNM (classification of malignant tumors and the extent of
spread of cancer) stage, or histological subtype [77].
The most common of all upper urinary tract cancer are those found in the renal pelvis
and renal calices. Cancer in the ureters makes up about a quarter of all upper urinary tract
cancer. Tumors of the renal calices, renal pelvis and ureters start in the layer of tissue that
lines the bladder and the upper urinary tract. Bladder cancer is a common solid tumor
marked by high rates of recurrence, especially in non-muscle invasive disease. Inhibition of
COX enzymes by NSAIDs results in reduced PGE2 levels, which is related with reductions
in the bladder cancer [78]. Clinical trials using NSAIDs to prevent recurrence have had
mixed results, but largely converge on issues with cardiotoxicity.

2.7. Prostaglandins in Nervous System Cancer

Nervous system cancer is the second leading type of cancer in children, after leukemia.
Cancer of the nervous system involves tumors that form in one or more parts of the
nervous system. Neuroblastoma, extracranial solid tumor of the sympathetic nervous
system, mainly affects young children. Neuroblastoma is a cancer located in the adrenal
medulla nerve cells of the body or other nervous system tissues such as the adrenal glands,
around the spinal cord or in the abdomen. Cancer-associated fibroblasts is the main source
of prostaglandin E2 in neuroblastoma contributing to angiogenesis, immunosuppression,
and tumor growth.
Some authors believe targeting of mPGES-1 in cancer-associated fibroblasts will be
an effective future therapeutic strategy in fighting neuroblastoma [79]. Several clinical
and experimental studies have demonstrated that regular use of aspirin (ASA) correlates
with a reduced risk of cancer and that the drug exerts direct anti-tumor effects. ASA could
be used as an adjunctive therapeutic agent in the clinical management of neuroblastoma,
although its effects appear to be mediated by a COX-independent mechanism involving an
increase in p21 and underphosphorylated retinoblastoma (hypo-pRb1) protein levels [80].
MicroRNA-137 (miR-137) plays an important role in the development and progression of
many types of human cancer. miR-137 was frequently down-regulated in retinoblastoma
tissues. MiR-137 suppresses the proliferation and invasion of retinoblastoma cells by
targeting COX-2/PGE2 . miR-137 could be used as a potentially effective therapeutic target
for the treatment of retinoblastoma [81].
Cancer of the nervous system might also affect the retina and it is called retinoblas-
toma or may affect the optic nerve and it is known as optic nerve glioma. Glioma, which is
a cancer that afflicts the brain stem, is the most common type of cancer accounting for 45%
of all brain cancer. There has been observed a direct and proportional relationship between
the concentration of prostaglandin PGE2 and the degree of malignancy in glioma tumors.
A higher concentration of PGE2 is related to greater cell proliferation and lower survival.
This PG binds to EP2 and EP4 receptors, thereby activating PKA-II, which in turn activates
CREB protein [82]. It has also been observed that PGE-EP4 binding stimulates the catabolic
tryptophan 2-3 dioxygenase (TDO) enzyme pathway, which promotes immunosuppression
by decreasing macrophages activation. The use of EP4 inhibitors decreases TDO activ-
ity [83]. Regarding prostaglandin PGD2 , it has been shown that high doses slow tumor
proliferation in glioma, but low concentrations seem to stimulate it [36]. On the other hand,
Cells 2021, 10, 1487 12 of 33

it has been shown that the use of 15d-PGJ2 in human neoplastic glioma cells produces an
increase in cell death, secondary to an increase in ROS production and activation of the
caspases pathway [35].

2.8. Prostaglandins in Immune Cancer

Dendritic cells (DC) differentiate in the presence of determined factors or situations
recognized as harmful, such as the onset of cancer. From the same progenitor, these cells
differentiate into classical DC (cDC) or plasmacytoid DC (pDC) depending on which
transcription factors are expressed. A study with mice showed that prostaglandin PGE2
synthesized in lymphoma cancer cells results in inhibition of ZBTB46 (zinc finger and
BTB Domain Containing 46) factor expression (only expressed in cDC), thus preventing
differentiation to cDC and favoring tumor expansion. In addition, the use of a COX-2
inhibitor, such as NS-398, resulted in functional cDC that reduced tumor burden [84].
Sperandio and coworkers demonstrated that treatment of multiple myeloma with
15d-PGJ2 produced a reduction in tumor cell proliferation without affecting non-neoplastic
cells both in vitro and in mice tumors. A dose-independent increase in apoptosis was also
observed in this study, which is probably related to the increased ROS concentration found
in 15d-PGJ2 -treated samples [85].
Acute lymphoblastic leukemia (ALL) develops in the bone marrow in the vicinity of
stromal cells known to promote tumor development and treatment resistance. The COX
inhibitor indomethacin prevents the ability of stromal cells to diminish p53-mediated
killing of cocultured ALL cells in vitro, and in a xenograft animal model, possibly by
blocking the production of PGE2 . PGE2 released by bone marrow stromal cells might be a
target for improved treatment of pediatric ALL. The indomethacin treatment increased the
level of p53 in the leukemic cells, implying that COX inhibition might reduce progression
of ALL by attenuating protective paracrine PGE2 signaling from bone marrow stroma to
leukemic cells [86]. Glucocorticoid resistance remains a clinical challenge in pediatric acute
lymphoblastic leukemia where response to glucocorticoids is a reliable prognostic indicator.
cAMP signaling synergizes with dexamethasone to enhance cell death in glucocorticoid-
resistant human T-ALL cells. The EP4 receptor expressed in T-ALL cells and PGE2 increases
intracellular cAMP, potentiates glucocorticoid-induced gene expression, and sensitizes
human T-ALL cells to dexamethasone in vitro and in vivo. [87].
On the other hand, an experiment performed with mice showed that the apoptotic
effect of selenium (Se) supplementation in leukemia cells depends on the concentration of
15d-PGJ2 ., which were analyzed in serum samples. Se activates the PPARγ pathway in vitro
and in vivo assays, which reduces STAT-5 (signal transducer and activator of transcription
5) levels and blocks the expression of the CITED2 (cAMP-responsive element-binding
protein (CBP)) gene, one of the responsible genes for tumor quiescence [88].

2.9. Prostaglandins in Endocrine Tissue Cancer

Endocrine cancer is found in tissues of the endocrine system, which include the
thyroid, adrenal, sexual glands, and pituitary glands. Pituitary adenomas are multifactorial
intracranial neoplasms that impose a massive burden of morbidity on patients. A study
demonstrated that COX-1 and COX-2 expression levels were increased in pituitary tumors
from human patients, including non-functional pituitary adenomas, acromegaly, Cushing’s
disease and prolactinoma compared with normal pituitary tissues. The level of PGE2
was consistent with COX enzymes expression in pituitary adenoma tumors compared
with healthy pituitary tissue. These results may open new molecular targets for early
diagnosis/follow up of pituitary tumor growth [89].
The cyclooxygenase-2 (COX-2)-prostaglandin E2 (PGE2 ) pathway with BRAF
(serine/threonine-protein kinase B-Raf) mutation was shown to promote PGE2 synthesis.
A study shows that COX-2 plays a key role in prognosis of Middle Eastern papillary thy-
roid carcinoma patients, especially in BRAF-mutated tumors. They suggest the potential
therapeutic role of COX-2 inhibition in patients with BRAF-mutated papillary thyroid car-
Cells 2021, 10, 1487 13 of 33

cinoma [90]. It has been also observed that the use of prostaglandin 15d-PGJ2 on papillary
thyroid cancer cells produces an increase in ROS due to the accumulation of intracellular
iron, which triggers tumor cell apoptosis [36].
Regarding the male reproductive system, AKR1C3 protein appears to play a key role
in androgen synthesis in prostate cancer cases. It has been shown that in AKR1C3+ cases,
the concentration of 17β-HSD (17β-hydroxysteroid dehydrogenase) is high. This molecule
can be blocked by androgen receptor (AR) antagonists, such as enzalutamide but in the
final stage of this disease, this effect disappears due to the mutation of the target protein of
the AR antagonist: TMPRSS2 (transmembrane protease, serine 2)-ERG (ETS (erythroblast
transformation-specific)-related gene) [91]. Increased expression of AKR1C3 has also been
associated with elevated concentrations of the prostaglandin PGF2α , which activates the
MAPK pathway and inhibits the PPARγ pathway. All these events favor proliferation and
tumor resistance of prostate cancer to radiotherapy. The use of indomethacin suppresses
AKR1C3 and eliminates this resistance [92].
Prostaglandin PGE2 has been shown to increase the migration and invasiveness of the
prostate cancer through activation of PI3K/AKT/mTOR and matriptase pathways. The use
of COX-2 inhibitors such as CAY10404 and celecoxib has the opposite effect. In addition,
prostaglandin 15d-PGJ2 acts as a tumor suppressor by inhibiting AR [93,94]. Finally, a
cohort study with 50 patients showed that higher COX-2 levels were significantly associated
with higher PSA (prostate-specific antigen), higher Gleason grade, worse prognosis, higher
probability of relapse after treatment, and shorter survival time [95].
Endometrial and ovarian cancer represent most gynecological malignancies in de-
veloped countries. Personalized treatments for this cancer depend on identification of
prognostic and predictive biomarkers that allow stratification of patients. A study evalu-
ated the level of AKR1C3 in endometrial cancer and ovarian cancer and examined possible
correlations between expression of AKR1C3 and other clinical and pathological data [96].
Thus, the expression of AKR1C3 was higher in endometrial cancer compared to ovarian
cancer. In endometrial carcinoma, high AKR1C3 expression correlated with better overall
survival and with disease-free survival. In patients with ovarian cancer, there was no corre-
lation between AKR1C3 expression and overall and disease-free survival or response to
chemotherapy. These results demonstrate that AKR1C3 is a potential prognostic biomarker
for endometrial cancer. Another study showed that the binding of the prostaglandin
PGF2α to its receptor favors the proliferation and migration of tumor cells in patients with
endometrial cancer [45]. On the other hand, prostaglandin PGJ2 has been shown to have
inhibitory effects on endometrial tumor cell proliferation [91].
It has been established that an increase in prostaglandin PGE2 provides ovarian tumor cells
with increased resistance to chemotherapy [97]. There is a known link between low expression
of RGS10 (regulator of G-protein signaling 10), a G-protein modulator of prostaglandin action,
and increased resistance to chemotherapy treatment in ovarian cancer. The loss of functional
RGS10 results in an increase in COX-2 concentration and thus an increase in prostaglandin
PGE2 synthesis, which leads to the conclusion that RGS10 inhibits COX-2. However, this
inhibition seems to be independent of its action on G proteins, since when inhibitors of this
protein were used, no increase in the concentration of inflammatory markers was observed, so
that the specific mechanism of inhibition has not yet been fully determined.
Even though in general cancer cases an increase in COX-2 levels is more common, it
is very interesting that in the case of ovarian cancer a higher concentration of COX-1 is
observed, which is why it has been suggested as a biomarker for early diagnosis. It has
been proposed to use COX-1 inhibitors such as [18F]-fluorin and [18F]-P6 as tracers to
detect ovarian cancer when performing PET (positron emission tomography). Furthermore,
it has been shown that the treatment effect is increased with placitaxol combined with
a selective COX-1 inhibitor (SC-560). It can be concluded that COX-1 inhibitors favor
chemosensitivity of ovarian cancer [98].
To identify biomarkers that could predict response or lack of response to conventional
chemotherapy at the time of diagnosis of high grade serous ovarian carcinoma, a study
Cells 2021, 10, 1487 14 of 33

showed that evaluation of PGD2 is an independent marker of good prognosis in this

carcinoma [99]. On the other hand, infection by human papillomavirus (HPV) serotype 16
is associated with an increase in COX-2 synthesis, which may be related to cases of cancer
associated with these infections [100].

2.10. Prostaglandins in Other Cancer

COX-2 is activated in response to inflammatory stimuli, and it can mediate its tumorigenic
effect through various mechanisms, such as inducing cell proliferation, inhibition of apoptosis,
and suppressing the host’s immune response. Furthermore, COX-2 can induce the production
of vascular endothelial growth factors, hence, promoting angiogenesis. The ability of COX-
2 inhibitors to selectively restrict the proliferation of tumor cells and mediating apoptosis
provides promising therapeutic targets for cancer patients. It is believed that COX2 can promote
the development and progression of head and neck cancer. Therefore, COX2 inhibitors could
be promising therapeutic weapons to fight the cancer [101].
EMT and angiogenesis are crucial events for development of aggressive and often fatal
oral squamous cell carcinomas. Both processes promote cancer progression and metastasis
development, but while the former induces the loss of E-cadherin expression; the latter
produces blood vessel neoformation and contribute to cell growth, tumor mass development,
and dissemination. COX-2 decreases the expression of E-cadherin and leads to phenotypic
changes in epithelial cells enhancing their carcinogenic potential. This study was performed
by a tissue microarray of oral squamous cell carcinomas from human patients [102].
An experiment with 180 mice demonstrated the potential of an EP-4 receptor inhibitor
such as GW627368X to reduce PGE2 expression in sarcomas treatment [103]. This treatment
resulted in reduced tumor volume and weight, and induction of apoptosis with increased
levels of BAX (BCL-2-like protein 4) and AIF (apoptosis-inducing factor) along with low
levels of Mcl-1 (induced myeloid leukemia cell differentiation protein) and Bcl-2 (apoptosis
regulator). Moreover, this treatment did not cause systemic toxicity, immunosuppression,
or behavioral changes.
Fibroblasts induce a high expression of COX-2, which leads to increased synthesis of
PGs that promote the secretion of fibroblast growth factor (FGF) and vascular endothelial
growth factor (VEGF), thus generating a continuous positive feedback. One study shows
that the use of DAPS (2,5-diacetyloxyphenylsulfonate), an inhibitor of FGF and VEGF
secretion, stops angiogenesis and tumor cell expansion in mice [104].

2.11. Prostaglandins in Tumor Microenvironment and Metastasis

The main reason cancer is such a serious illness is because of its ability to spread in
the body. Cancer cells can spread locally by moving within the surrounding normal tissue.
Cancer can also spread regionally, to nearby lymph nodes, tissues, or organs, and it can
also spread to distant parts of the body. When this happens, it is called metastatic cancer or
metastasis. For many types of cancer, this is called stage IV cancer. The transformation of a
tumor cell into a metastatic tumor cell probably involves transient or permanent genetic
changes, which determine the expression of molecules with actions that favor or protect
the mechanisms necessary for metastasis. The most frequent locations of metastases are
the organs most irrigated by blood, such as the brain, lungs, liver, bones, and adrenal
glands. There is also a tendency for certain tumors to spread in certain organs. For example,
prostate cancer tends to spread through the bones. Likewise, colon cancer does so in the
liver and stomach cancer in the ovaries in the case of women. The cancers that metastasize
the most are the most frequent cancers such as breast cancer, lung cancer, melanoma, and
colorectal cancer.
Tumorigenesis is a multistep biological process and many studies have been focused
on the critical role of the tumor microenvironment (TME). The tumor microenvironment
plays a major role in the ability of the tumor cells to undergo metastasis. Tumor cells along
with a small proportion of cancer stem cells exist in a stromal microenvironment consisting
of vasculature, cancer-associated fibroblasts, immune cells, and extracellular components.
Cells 2021, 10, 1487 15 of 33

A major player of tumors gaining metastatic property is the inflammatory protein

COX-2. Several tumors show upregulation of this protein, which has been implicated in
mediating metastasis in various cancer types such as of colon, breast, and lung. COX2
has been closely linked to the occurrence, progression, and prognosis of cancer in tumor
microenvironment [105]. It has also been shown that an abnormally high expression of
the COX-2 enzyme leads to an increase in the concentration of the different PG subtypes,
which favor or hinder different aspects of carcinogenesis. 15-Deoxy-∆12,14-prostaglandin
J2 (15d-PGJ2) is a prostaglandin whose effects depend on its concentration and the cell
type in which it is found. Its effects include a decrease in angiogenesis and favoring
of the apoptosis process. Prostaglandin 15d-PGJ2 produces an increase in ROS through
mitochondrial dysfunction, activation of NADPH (Nicotinamide adenine dinucleotide
phosphate) oxidase and JNK, and inhibition of AKT, which favors tumor apoptosis through
the TRAIL (TNF-related apoptosis-inducing ligand) pathway associated with an increase
in the concentration of the DR5 receptor, through a mechanism independent of the PPARγ
pathway [36]. This activates PI3K-Akt signaling in human breast cancer cells through cova-
lent modification of the tumor suppressor PTEN at cysteine 136 [46]. One study has shown
that PGE2 favors the angiogenesis process for the supply of oxygen and nutrients necessary
for tumor progression. The use of 3-(3-methylthiophen-2-yl)-5-(3,4,5-trimethoxyphenyl)
isoxazole (2b) showed significant inhibitory activity toward COX-2 and showed a good in-
hibition of tumor growth, peritoneal angiogenesis, and ascites formation in Ehrlich ascites
carcinoma (EAC) cell mouse model [106].
Increased levels of ATP in the tumor microenvironment in response to cell death medi-
ated by chemotherapeutic agents such as doxorubicin leads to increased COX-2 expression,
which, in turn, affords migratory and invasive properties to the tumor. Anti-inflammatory
drugs against ATP receptors is a potential opportunity to be explored as cancer therapeu-
tics [107]. Recent epidemiological and clinical studies strongly support the assertion that
vitamin D supplementation is associated with reduced cancer risk and favorable prognosis.
Experimental results suggest that vitamin D not only suppresses cancer cells, but also
regulates tumor microenvironment to facilitate tumor repression [108]. Another study
with mice showed that an increased intake of omega-3 and omega-6 polyunsaturated
fatty acids reduced tumor growth in the melanoma microenvironment, along with a lower
concentration of prostaglandins PGE2 and PGE3 [109].
The hypothesis that the anti-inflammatory activity of NSAIDs should be based on
COX inhibition is well established in multiple experimental models, and NSAIDs are one
of the therapeutic tools used in the current clinical fight against cancer, combined with
other therapies. Thus, COX-2 inhibitors can reduce inflammatory factors thereby regu-
lating macrophage recruitment for activating the antitumor immune microenvironment;
downregulating vascular endothelial growth factor (VEGF) to inhibit tumor angiogenesis;
and inhibiting the PI3K/Akt signaling pathway to induce tumor cell apoptosis. However,
further in-depth investigation of these drug is needed to maximize antitumor efficacy and
minimize the side effects [110,111].
The molecular and cellular mechanisms that cancer cells use to spread to other organs
are diverse and complex. Thus, activation of PPARγ serves as a key factor in the proliferation
and invasion of breast cancer cells and it is a potential therapeutic target for breast cancer.
Heme oxygenase-1 (HO-1) is induced and overexpressed in various types of cancer and is
associated with features of tumor aggressiveness. Recent studies have shown that HO-1 is a
major downstream target of PPARγ. Jang and coworkers suggest that 15d-PGJ2 inhibits MMP9
expression and invasion of breast cancer cells by means of a heme oxygenase-1-dependent
mechanism. Therefore, PPARγ/HO-1 signaling pathway inhibition may be beneficial for
prevention and treatment of breast cancer and its metastasis [112].
The host stromal mPGES-1 is involved in the accumulation of myeloid-derived sup-
pressor cells (MDSCs) in metastasized lungs of prostate cancer in mice. mPGES-1 enhances
tumor metastasis in mice by inducing accumulation of BM (bone marrow)-derived MDSCs.
Selective mPGES-1 inhibitors might, therefore, represent valuable therapeutic tools for
Cells 2021, 10, 1487 16 of 33

the suppression of this tumor metastasis [113]. Prostaglandin 15d-PGJ2 has the ability to
decrease breast and renal cancer metastasis, since it produces a reduction in the synthesis of
extracellular matrix proteins (MMP), such as MMP-2 and MMP-9, which minimizes the in-
vasiveness of these tumor cells [35]. Also, less melanoma metastasis has been demonstrated
in mice with elevated concentrations of PGD2 [36]. By contrast, another study with patients
showed that a higher concentration of PGE2 is significantly related to a higher expression
of metalloprotease-1 (MMP1), which facilitates the transfer of cancer cells through the
hematoencephalic membrane, and with it, the appearance of brain metastasis of breast
cancer [114]. Similarly, prostacyclin (PGI2 ) has been shown to have great relevance as a
tool to stop the development of tumor metastases [115]. Finally, the use of intraopera-
tive injections of Etodolac (a NSAID) and propranolol in mice has been shown to reduce
the number of colon cancer liver metastases by activating NK cells. However, neither
compound separately obtained significant results [116].
Cervical cancer metastasis results in poor prognosis and increased mortality, which is
not separated from inflammatory reactions accumulated by PGE2 . As a specific G-protein
coupled PGE2 receptor, EP3 is demonstrated as a negative prognosticator of cervical
malignancy. EP3 signaling pathway might facilitate the migration of cervical cancer cells
through modulating uPAR (urokinase plasminogen activator surface receptor) expression.
Therefore, EP3 and uPAR could represent novel therapeutic targets in the treatment of
cervical cancer in advantaged stages [117].
The ability of the immune system to recognize and eliminate tumor cells is called
immune surveillance. One of the functions of the immune system is to recognize and
destroy tumor cells before they grow and form a cancer, as well as to eliminate tumors that
have already formed. At first, the results of some experiments questioned the importance
of immune surveillance, but today it is clear that the immune system reacts to many
tumors. This knowledge has led to the immune response being seen as another therapeutic
weapon in the treatment of cancer. MDSCs include immature monocytic (M-MDSC) and
granulocytic (PMN-MDSC) cells that share the ability to suppress adaptive immunity
and to hinder the effectiveness of anticancer treatments. In response to IFNγ (interferon
gamma), MDSCs release the tumor-promoting and immunosuppressive molecule nitric
oxide (NO), whereas macrophages largely express antitumor properties. A study indicates
that inhibition of the PGE2 /p50/NO axis prevents MDSC-suppressive functions and
restores the efficacy of anticancer immunotherapy [118].
Immune checkpoint inhibitors improve survival outcomes in metastatic melanoma
and non-small cell lung cancer. Preclinical evidence suggests that overexpression of cyclo-
oxygenase-2 (COX2) in tumors facilitates immune evasion through prostaglandin E2 pro-
duction and that COX inhibition synergizes with immune checkpoint inhibitors to promote
antitumor T-cell activation. COXi inhibitor used concurrently with immune checkpoint
inhibitors in human patients significantly associated with longer time-to-progression and
improved objective response rate at 6 months in patients with metastatic melanoma and
non-small cell lung cancer compared with Immune checkpoint inhibitors alone [119]. Fur-
thermore, COXi inhibitor use appears to reverse the negative prognostic effect of a high
neutrophil-lymphocyte ratio by prolonging time-to-progression in patients with melanoma.
Resistance to immunotherapy is one of the biggest problems of current oncothera-
peutics. White T cell abundance is essential for tumor responsiveness to immunotherapy,
factors that define the T cell inflamed tumor microenvironment are not fully understood.
Markosyan and coworkers demonstrated in mice that tumor cell-intrinsic EPHA2 sup-
presses anti-tumor immunity by regulating PTGS2 (COX-2) in pancreatic adenocarci-
noma [120]. Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are
pathologically activated neutrophils that are crucial for the regulation of immune responses
in cancer. These cells contribute to the failure of cancer therapies and are associated with
poor clinical outcomes. A work demonstrated that mouse and human PMN-MDSCs ex-
clusively upregulate fatty acid transport protein 2 (FATP2). Thus, FATP2 mediates the
acquisition of immunosuppressive activity by PMN-MDSCs and represents a target to
Cells 2021, 10, 1487 17 of 33

inhibit the functions of PMN-MDSCs selectively and to improve the efficiency of cancer
therapy [121]. The initiation of an intestinal tumor is a probabilistic process that depends
on the competition between mutant and normal epithelial stem cells in crypts. Intesti-
nal stem cells are closely associated with a diverse but poorly characterized network of
mesenchymal cell types. One study performed in humans and mice demonstrates that
initiation of colorectal cancer is orchestrated by the mesenchymal niche and reveals a
mechanism by which rare pericryptal Ptgs2-expressing fibroblasts exert paracrine control
over tumor-initiating stem cells via the druggable PGE2 -PTGER4-YAP signaling axis [122].
Table 2 summarizes some of the data observed in the different studies analyzed, which
could help to plan new research.
Cells 2021, 10, 1487 18 of 33

Table 2. Summary of the role of prostaglandins in cancer. In red: cellular, molecular factors or treatments that promote the development of cancer. In blue: cellular, molecular factors or
treatments that hinder tumor progression.
Type of Cancer and Cellular-Molecular
Tissue/Organ Molecular/Cellular Effect Physiological/Pathological Impact
Scenario Factors/Therapeutics
PGD2 decrease.
AKR1C3+ PGF2α increase
Promotion of neovascularization
15d-PGJ2 Inhibition of STAT-3 pathway Reduction of cell growth
Squamous PGI2 increases Higher 5-year survival rate
ACOX-1 decrease.
miR-31-5p increases Increase of tumor migration and invasion
PGE2 increase
Skin
PGE2 PGE2 increase, larger stage Possible biomarker of progression?
Apigenin COX-2 and PGE1 -EP1/EP2 decrease Inhibition of neoplastic progression
Non-melanoma
Piroxicam COX-2 decrease Useful in prevention
PGF2α Blocking AAS action Prevention of tumor apoptosis
Melanoma PGF2α antagonist Inhibition of ASA blockade Promotion of tumor apoptosis
Inhibition of COX-2 expression and PGE2 Inhibition of the migration, invasion, and
Topical Melanotan II
production colony-forming capability
Antitumor strategy using COX2 inhibitors.
SND1 Increase of PGE2
Potential biomarker of the therapeutic
Bones Osteosarcoma
strategies
PGE2 Increase of proliferation and decrease of
EP1 pathway
17-PT-PGE2 apoptosis of cells
CRTC1+ /LKB1− Activation of cAMP/CREB y PGE2 Promotion of tumor development
CRTC1+/LKB1 cancer
Niflumic acid (NS-398) PGE2 decrease Hindrance of tumor development
Decrease of CUGBP1 and increase of
miR-574-5p Promotion of tumor development
mPGES-1 and PGE2
Non-small cell cancer 15d-PGJ2
Increase of ROS and activation of caspases Increase of apoptosis
PGD2
Lungs
mPGES-1 inhibitors PGE2 decrease Cancelation of miR-574-5p effects
MHC-II+ lung cancer PGIs Increase of T-CD4+ lymphocytes Inhibition of tumor growth
Prediction of poor patient survival.
Primary lung tumors ACSL3 Increase of LPIAT1 activity
Anchorage-independent growth
Lung squamous cell PGE2
Activation of TNF-alpha-TRAF2-MMP-9 Progression of lung cancer
carcinoma TNF-alpha
General lung cancer NSAIDs Inhibition of COX enzymes Smaller tumor size and fewer metastasis.
Cells 2021, 10, 1487 19 of 33

Table 2. Cont.
Cellular-Molecular
Tissue/Organ Type of Cancer and Scenario Molecular/Cellular Effect Physiological/Pathological Impact
Factors/Therapeutics
AKR1C3+ PGF2α - FP and Ki-67 increase Increase of cell proliferation
AKR1C3 inhibitor PGF2α decrease Reduction of cell expansion
Activation of ERK1/2-MAPK pathway
PGF2α -FP increase and Increase of resistance to QT
activation of NF-κB
FP inhibitor Inhibition of ERK1/2-MAPK pathway
Reduction of resistance to QT
NF-kB inhibitor Inhibition of NF-κB factor
15d-PGJ2 Activation of AKT-AP-1 pathway Promotion of tumor expansion.
Mammary gland Breast cancer
Up-regulation of Snail and CXCL8 Epithelial-to-mesenchymal transition (EMT).
15d-PGJ2
expression Tumor-stroma interaction
Oxidative stress and subsequent damaging of
8-iso-PGF2α Serum non-invasive marker
DNA
C136S-PTEN (mutated) Not affected by 15d-PGJ2 Resistant?
Decrease of tumor migration and invasion.
DGLA * Activation of caspases, PARP and COX-2 Greater efficacy of treatment with
5-fluouracil.
PGE2 -EP2 increase CD80 decrease on macrophages Reduced macrophage polarization
PGESm-1 Knock out PGE2 -EP2 decrease and CD80 increase Normal macrophage polarization
PGI2 increase Shorter survival time
Less tumor volume (dose-dependent), more
mature macrophages, more CD-45+
Ibuprofen PGE2 decrease
T-lymphocytes, and fewer immature
monocytes
Less tumor dissemination, more NK
Propanolol + Etodolac (Peri-QX) Inhibition of STAT and EGR3 pathways lymphocytes, more B cells, fewer monocytes,
and less IL-6.
Fewer regulatory T-lymphocytes, more
Increase of stellate cells COX2-PGE2 -EP4 increase
MDSCs
HCC SC-236 (COX-2 inhibitor)
Liver Stellate cells ** decrease Stop the spread of cancer
AH23848 (EP4 inhibitor)
EP4-G-Adenylate increase and activation
PGE2 of cyclase-cAMP-kinase A-CREB pathway Facilitation of tumor expansion
and oncogene MYC
Hepatitis B virus DMC combined with atezolizumab: more
2,5-dimethylcelecoxib (DMC). Inhibition of microsomal prostaglandin E
(HBV)-related hepatocellular antitumor effect and stronger blockage of
PD-L1 synthase-1 (mPGES-1)/PGE2 production
carcinoma (HCC). immunosuppression effect on PD-L1
Cells 2021, 10, 1487 20 of 33

Table 2. Cont.
Cellular-Molecular
Tissue/Organ Type of Cancer and Scenario Molecular/Cellular Effect Physiological/Pathological Impact
Factors/Therapeutics
Esophageal squamous cancer ZIP5 inhibitor Cyclin D1 decrease. COX-2 increase Metastasis reduction
H. pylori COX-2 increase Promotion of the onset of neoplasia
NSAIDs Inhibition of COX Effective prophylaxis
Gastric adenocarcinomas
PGD2 PPARγ decrease Slower growth
15-PGDH FOXP3 Anti-tumor immunity
Inhibition of PI3K-AKT-mTOR and
EP4 inhibitors Reduction of the number of new adenomas
ERK1/2-MAPK pathways
Adenoma
ASA as prophylactic (75–325 mg) Fewer adenomas and lower mortality
Fewer new adenomas and more
Sulindac (15-PGDH knock-out)
inflammatory lesions
Prevention of carcinogenesis. Increase in the
COX2 Inhibition of COX2 survival rate.
Digestive system
Risk of cardiovascular complications with
prolonged treatment
Targeting the TME Downstream molecules of PGE2 signaling Promising approach
PGF2α Increased migration and invasion
MYC modulation and telomerase
15d-PGJ2 Increased rate of cell death
inhibition
Colorrectal cancer Increase of CREB/AP-1, COX-2 and
CRTC1 Promotion of tumor development
aaPGE2
IP6 Hindrance of tumor development
Decrease of COX-2 and PGE2
NSAIDs Reduction of tumor mass and metastasis
AAS (Stage III) Lower mortality and relapses
AAS + Statins PG decrease
Increase of EGR1 factor and
PGF2β Promotion of tumor progression
prostaglandin synthase E enzyme
Decrease of EGR1 factor and
PGF2β inhibitor Hindrance of tumor progression
prostaglandin synthase E enzyme
Tumor suppressor Knock-out.
Increased resistance to ASA and celecoxib
15-PGDH
Elevated levels: patients already
PGM increase diagnosed > patients with multiple Early diagnostic marker?
adenomas > healthy controls.
XRCC5 protein p300 and COX-2 increase Promotion of tumor progression
p300 inhibitor COX-2 decrease Hindrance of tumor progression
Cells 2021, 10, 1487 21 of 33

Table 2. Cont.
Cellular-Molecular
Tissue/Organ Type of Cancer and Scenario Molecular/Cellular Effect Physiological/Pathological Impact
Factors/Therapeutics
Not very useful, since they do not express
AAS
COX-1.
Pancreas Pancreatic cancer
Possible adjuvant treatment for cisplatin +
Celecoxib COX-2 decrease
gemcitabine?
Decreased cancer-associated fibroblasts
Vitamin D3 analogues: calcipotriol PD-L1 upregulation proliferation and migration. Reduced release
of PGE2.
Activation of caspases, and JNK and AKT
15d-PGJ2 kinases. Intracellular Promotion of apoptosis
[Ca2+ ] increase
Kidney Renal cancer
COX-1 increase Higher degree of malignancy
Not related to tumor size, Fuhrman grade,
PGE2 increase
TNM stage or histological subtype.
Activation of cAMP/PKA II-COX2
Cadmium Mediated cell migration and invasion
pathway and N-Catherin expression
Urinary system Bladder cancer
Increase of proliferation and decrease of
PGE2 -EP2 PKA-II and CREB increase
survival
PGE2 -EP4 TDO decrease Reduction of macrophage activation
Glioma
PGD2 increases Reduction of tumor proliferation
Nervous system
PGD2 decreases Increase of tumor proliferation
15d-PGJ2 ROS and caspases increase Increase of cell death
COX-independent mechanism involving
Neuroblastoma ASA an increase in p21 and Adjunctive therapeutic agent
underphosphorylated hypo-pRb1.
Retinoblastoma MicroRNA-137 Inhibition of COX-2/PGE2 Suppression of proliferation and invasion
ROS increase Increase of angiogenesis and promotion of
15d-PGJ2
Multiple Myeloma via PPARγ decrease apoptosis
Increased intake of omega-3 and
PGE2 y PGE3 decrease Reduction of tumor growth
omega-6 polyunsaturated fatty acids
Avoid the stromal cells diminished
Immune system
Indomethacin p53-mediated killing. Reduction of progression of ALL
Acute lymphoblastic leukemia
Blockage of the production of PGE2
(ALL)
EP4 receptor Sensitizes human T-ALL cells to
Increase of intracellular cAMP
PGE2 dexamethasone
Cells 2021, 10, 1487 22 of 33

Table 2. Cont.
Cellular-Molecular
Tissue/Organ Type of Cancer and Scenario Molecular/Cellular Effect Physiological/Pathological Impact
Factors/Therapeutics
Activation of PPARγ. Inhibition of
Selenium supplements
General Leukemia STAT-5 and CITED2 Apoptotic effect
Increase of ROS-NADPH oxidase.
15d-PGJ2 Activation TRAIL-JNK.
Inhibition of AKT
PGE2 Factor ZBTB46 decrease Prevention of differentiation to cDC
Lymphomas
PGE2 decrease and
NS-398 Tumor burden reduction
cDC increase
Pituitary adenomas COX1/2 PGE2 Promotion of tumor progression
15d-PGJ2 [Fe2+ ] intracellular and ROS increase Promotion of tumor apoptosis
Papillary thyroid cancer
BRAF-mutated tumors promote PGE2
COX2 and PGE2 Promotion of tumor progression
synthesis
Increase of PGF2α and activation of
AKR1C3+
MAPK pathway. Increase of proliferation and resistance to
17β-HSD Inhibition of PPARγ radiation therapy

Prostate cancer Androgen receptor antagonists, Indomethacin suppresses AKR1C3 and

Blockage of 17β-HSD
such as enzalutamide eliminates resistance
Endocrine tissues Activation of PI3K/AKT/mTOR and
PGE2 -EP1/EP2 Increase of migration and invasion
matriptase pathways
PGE2 decrease.
CAY10404 and celecoxib Inhibition of PI3K/AKT/mTOR Decrease of migration and invasion
and matriptase pathways
15d-PGJ2 Inhibition of AR Tumor suppressor
Poorer prognosis, more relapses, and poorer
COX-2 increase PSA and Gleason increase
survival.
PGF2α More proliferation and migration
Endometrial cancer AKR1C3+ Better overall survival Prognostic biomarker
PGJ2 Reduction of proliferation
RGS10 decrease COX-2 and PGE2 increase More resistance to chemotherapy
COX-1 *** increase Early diagnostic biomarker?
Ovary cancer
COX-1 inhibitors ([18 F]-Fluorine y
Trackers when performing a PET scan?
[18 F]-P6)
SC-560 Increased chemosensitivity
Serous ovarian carcinoma PGD2 Marker of good prognosis
Cells 2021, 10, 1487 23 of 33

Table 2. Cont.
Cellular-Molecular
Tissue/Organ Type of Cancer and Scenario Molecular/Cellular Effect Physiological/Pathological Impact
Factors/Therapeutics
HPV serotype 16 infection COX-2 increase Related to the onset of cancer?
Negative prognosticator of cervical
Cervical cancer PGE2 receptor, EP3 Modulation of uPAR expression
malignancy
Reduction of tumor volume and weight.
BAX and AIF increase.
GW627368X (EP4 inhibitor) Induction of apoptosis
Sarcoma MCL-1, BCL-2 and PGE2 decrease
Other tissues Fibroblasts COX-2, PGE2 , FGF and VEGF increase Increase of angiogenesis and tumor spread
DAPS FGF and VEGF decrease Decrease of angiogenesis and tumor spread
Protumorigenic effect.
Head and neck cancers COX-2 Various mechanisms
COX-2 selective inhibitors
Oral squamous carcinomas COX-2 Loss of E-cadherin expression EMT and angiogenesis
COX-2. PGE2 , ATP Increased angiogenesis Supply of O2 and nutrients.
All
Decrease of cancer risk and favorable
Vitamin D Sensitivity to NSIAIDs targeting PGE2
prognosis
Breast cancer CXCL8 Activator of fibroblasts, Tumor-stroma interaction in TME
Promotion of HBV-related HCC immune Combined immunotherapy with DMC and
Liver cancer 2,5-dimethylcelecoxib (DMC)
TME atezolizumab
Pancreatic adenocarcinoma EPHA2 PTGS2 (COX-2) Suppression of anti-tumor immunity
PMN-MDSCs Increase of FATP2 Immunosuppressive activity
TME/Metastasis/Immune
Intestinal tumor Mesenchymal niche PGE2 -PTGER4-YAP signaling axis Initiation of colorectal cancer
surveillance
PGE2 MMP1 increase More brain metastases
Breast cancer PGI2 Stops its development
Inhibition of MMP9 through Prevention and treatment of breast cancer
15d-PGJ2
PPARγ/HO-1 signaling pathway and its metastasis
Prostate cancer mPGES-1 Accumulation of BM-MDSCs in lungs Use of Selective mPGES-1 inhibitors
Renal cancer 15d-PGJ2 MMP decrease Reduction of invasiveness
Melanoma PGD2 Lower number of metastasis
Melanoma and non-small cell
COX1/2 inhibitors Lower number of metastasis
lung cancer
Colorectal cancer Etodolac + Propanolol Lymphocytes NK increase Reduction of tumor progression
Immune System Immune surveillance Immune system reacts to many tumors. Therapeutic weapon to eliminate tumor cells
M-MDSC Increase of NO Suppression of adaptive immunity. Inhibition of the PGE2 /p50/NO
* After inhibiting the enzyme delta-5-desaturase (whose function is to convert DGLA into arachidonic acid). ** Only in vitro assays. *** Although in cancer COX2 is usually increased, in this case there is a very
striking increase in COX-1.
Cells 2021, 10, 1487 24 of 33

3. Conclusions
According to the data revised in this work, the involvement and importance of PGs in
the development of different neoplasms is more than evident. The effects of prostaglandin
in cancer depends on multiple factors, such as the target damaged tissue, the plasma
concentration of prostaglandins and their subtypes, and the presence of genetic mutations
and the different intracellular signaling pathways involved, will tip the balance either
towards tumor regression or cancer expansion.
Prostaglandins of the PGD2 type are clearly related to better survival expectations,
since they can hinder tumor progression. In all the evidence reviewed, it can be observed
that a higher concentration of the prostaglandin PGD2 is associated with a greater difficulty
for the tumor to progress, either as a primary tumor or as metastasis, and with increased
apoptosis of cancer cells. However, a low concentration of this prostaglandin does not
protect against tumor development. Therefore, PGD2 can be considered as a protective
factor against cancer and a marker of good prognosis.
PGE2 and PGF2α prostaglandins are related to greater tumor progression and aggres-
siveness, also associated with a worse functioning of the immune system. With respect to
PGE2 , all the references found seem to point to it as a prostaglandin that facilitates tumor
development by activating different signaling pathways. The action of this prostaglandin
results in greater vascularization, greater ease of metastasis, and less maturation of immune
system cells capable of halting its advance, like macrophages polarization and activation,
although it sensitizes human T-ALL cells to dexamethasone. Therefore, it could be said that
a high amount of PGE2 is a risk factor to be considered in tumor origin and progression. In
fact, some of the authors propose using the measurement of its levels as a biomarker of
neoplastic evolution. Everything seems to indicate that the prostaglandins PGF2α is one of
the factors responsible for the resistance of different types of cancer to some of the thera-
peutic options, such as the use of ASA or chemotherapy. In addition, this prostaglandin has
been related to a greater capacity for cancer migration and invasion and prevents tumor
apoptosis. Therefore, elevated PGF2α concentration could be considered a risk factor for
neoplastic progression. Also, PGF2β facilitates tumor progression in some neoplasms such
as colorectal cancer.
Prostaglandins PGI2 and PGJ2 are generally related with the arrest of cancer devel-
opment, but since works point them out as possible inducing factors of neoplasia, further
research is necessary to clarify the contradictory data. Thus, there is some controversy in
the implication of prostaglandin PGI2 in cancer. Most scientific works show data that may
lead to the assumption that it acts as a protective factor against neoplastic development.
Thus, high concentrations of PGI2 are related to a lower number of metastases of any type of
cancer and a higher 5-year survival in squamous epithelial cancer by inhibiting lung tumor
growth. However, one research work demonstrates a significant relationship between a
high concentration of this PG and a lower survival in breast cancer. Therefore, determining
the role of this PG in the development of cancer is risky, so it would be advisable to study
its involvement in different types of cancer. As with prostaglandin PGI2 , the data on the
involvement of prostaglandin PGJ2 in cancer are also contradictory. Most of the works
suggests that PGJ2 has the capacity to inhibit tumor expansion, as it seems to facilitate
cancer cell apoptosis and hinder angiogenesis, proliferation, and invasion. However, some
other researchers propose that PGJ2 may promote tumor progression by inhibiting the
tumor suppressor PTEN activity in breast cancer.
In addition to the evidence found about the influence of the different subtypes of PGs
on the distinct types of cancer, it is necessary to make special mention of the function of
AKR1C3 protein that can determine the intensity of the effects of these lipid molecules on
tumor development. The presence of this protein has been related to a shift from the syn-
thesis of “potentially protective PGs”, such as PGD2 , towards the synthesis of “potentially
carcinogenic PGs”, such as PGF2α . This shift leads to increased tumor vascularization and
increased resistance to different therapeutic tools. For this reason, the AKR1C3 protein is
proposed as a possible and interesting therapeutic target. In fact, in some of the studies
Cells 2021, 10, 1487 25 of 33

reviewed, inhibitors of this enzyme are used, in which PGF2α levels are normalized and
tumor expansion is slowed down.
The use of different NSAIDs, especially selective COX-2 inhibitors, may have a crucial
role in the therapeutic strategy to end the origin and progression of neoplasms, either as a
prophylactic treatment in the population at risk, or as an adjuvant treatment to chemotherapy
or radiotherapy. Moreover, the analysis of the intracellular signaling pathways involved in
cancer and related to the action of prostaglandins has revealed multiple therapeutic targets in
addition to COX1/2 enzymes. Therefore, more detailed studies should be carried out to obtain
better therapeutic tools by combining treatments against cancer.
Given the great relevance of PGs in terms of the outcome of neoplasms, it would be
interesting to favor, by means of different genetic, biochemical, and molecular tools, the
reduction of the concentration of “potentially carcinogenic PGs”, such as PGE2 and PGF2α ,
and to increase the concentration of “potentially protective PGs”, such as PGD2 , PGI2 and
PGJ2 . Therefore, both the inhibition of the expression of the genes that code for COX enzymes,
and the use of specific inhibitors of these enzymes are good therapeutic strategies against
cancer, since they would reduce the concentrations of the different types of PGs.
On the other hand, the scientific studies reviewed also consider other therapeutic
possibilities, such as the use of PG receptor inhibitors. Despite the high concentrations of
PGs that may be present in plasma in a neoplastic process, the inhibition of their receptors
would avoid the binding of PGs to their receptors and PGs would not be able to produce any
effect on the nearby cells, with the result that the PGs would be destroyed without having
any repercussions. In addition, as described above, there are many signaling pathways that
interact with PGs. These interactions increase the number of possible therapeutic targets,
since it would be possible to block these connections at more points, at the genetic, molecular,
or cellular levels. Some examples of these potential targets analyzed are ZIP5, mPGES-1, FGF,
VEGF, XRCC5, PPARγ, AKT, ERK1/2 MAPK, NFκB, PTEN, or p300, among many others.
Finally, as described above, the studies should be also focused on the critical role of the
tumor microenvironment (TME) as a promoter of the ability of the tumor cells to undergo
EMT and metastasis. One of the major players in metastatic tumors is the inflammatory
protein COX-2 upregulated in several tumors, which lead to the production of PGs and the
development of the different aspects of carcinogenesis. As mentioned through this revision,
selective COX-2 inhibitors are preferred over an inhibitor of both isoforms to avoid the
side effects of COX-1 suppression. COX-2 selective inhibitors produce a reduction of PGs
together with the inhibition of tumor progression, either in extension or in the number of
tumors. The hypothesis that the anti-inflammatory activity of NSAIDs should be based on
COX inhibition is well established, and NSAIDs are one of the therapeutic tools used in
current clinical fight to cancers, combined with other therapies. Another factor to consider
in the fight against cancer is the immune surveillance or the ability of the immune system
to recognize and eliminate tumor cells, which has been seen as another therapeutic weapon
in the treatment of cancer.
It is important to clarify that data presented in this review, about the involvement of
prostaglandins in the different types of cancer, are observations made in vitro assays, by
using cell lines, in ex vivo assays, by using samples of tumorigenic tissues from animals
or humans, or in vivo experiments, made in animals, but few molecular and cellular data
have been confirmed in humans. Therefore, more detailed studies should be carried out
in humans to confirm the molecular and cellular events observed in animals or cell lines,
and to determine the appropriate concentrations of prostaglandins and their inhibitors to
use in human patients in order to develop safe single or polytherapy tools against cancer,
avoiding unwanted side effects as much as possible.

Funding: This research received no external funding.

Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Cells 2021, 10, 1487 26 of 33

Data Availability Statement: Data sharing not applicable.

Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations

Alpha-MSH alpha-melanocyte stimulating hormone

8-iso-PGF2α 8-Iso-prostaglandin F2 alpha
15d-PGJ2 15-deoxy-Delta (12,14)-prostaglandin J2
15-PGDH tumor suppressor 15-hydroxyprostaglandin dehydrogenase
17β-HSD 17β-hydroxysteroid dehydrogenase
17-PT-PGE2 17-phenyltrinor-prostaglandin E2
AA arachidonic acid
AC Adenylyl cyclase
ACSL3 long-chain acyl-CoA synthetase
ACOX-1 acilcoenzyme A peroxisomal A oxidase 1
AH23848 (4Z)-7-[(rel-1S, 2S, 5R)-5-((1,10 -Biphenyl-4-il) methoxy)
-2-(4-morfolinil) 3-oxocyclopentil]
AIF apoptosis inducer factor
AKR aldo-keto reductase enzymes
AKR1C3 aldo-keto reductase enzyme 1 C3
AKT protein kinase B (PKB)
ALL acute lymphoblastic leukemia
AML acute myeloid leukemia
AMPK AMP-activated protein kinase
ASA acetylsalicylic acid
AXAXB protein 4 similar to BCL2
BAX BCL-2-like protein 4
BAY11e7082 NF-kB inhibitor
BCL2 B-cell lymphoma 2
BM bone marrow
cAMP cyclic adenosine monophosphate
cAMP-kinase A cAMP-dependent protein kinase A (PKA)
Cd Cadmium
cDc classic dendritic cells
CD4 cluster of differentiation 4
CD45 leukocyte common antigen
CD80 cluster of differentiation 80
CITED2 cAMP-responsive element-binding protein (CBP)
COX1/2/3 cyclooxygenase 1/2/3
COXi COX inhibitor
COXIB2 (celecoxib) selective cyclooxygenase type 2 inhibitors
CREB cAMP response element-binding
CRTC1 transcriptional coactivator regulated by CREB1
CUGBP1 CUG triplet repeat, RNA binding protein 1
CXCL8 chemokine (C-X-C motif) ligand 8
CYP2C P450 arachidonic acid epoxygenase 2C
CYP4A cytochrome P450 4A fatty acid omega hydroxylase
CYP2J P450 arachidonic acid epoxygenase 2J
DAG diacylglycerol
DAPS 2.5-diacetyloxyphenylsulfonate
DC Dendritic cells
DGLA Dihomo-γ-linolenic acid
DHETE dihydroxyeicosatrienoic acid
DMC 2,5-dimethylcelecoxib
DP1 and DP2 PGD2 receptors
DR5 death receptor 5
Cells 2021, 10, 1487 27 of 33

EET epoxyeicosatrienoic acid

EGR1 early growth response protein 1
EGR3 early growth response protein 3
EMT epithelial-to-mesenchymal transition
EP1, EP2, EP3 AND EP4 PGE2 RECEPTORS
EPHA2 Ephrin type-A receptor 2
ER ESTROGEN RECEPTOR
ERG ETS-related gene
ERK1/2-MAPK extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase
ETS erythroblast transformation specific
FATP2 Fatty acid transport protein 2
FGF fibroblast growth factor
FOXP3 fork head box protein 3
FP PGF2a receptor
G guanine nucleotide-binding protein
G12 G protein that link cell surface G protein-coupled receptors primarily
to guanine nucleotide exchange factors for the Rho small GTPases
Gi G protein that transmits an inhibitory signal from membrane
receptors to adenylyl cyclase
Gs G protein that stimulates the cAMP-dependent pathway by activating
adenylyl cyclase
Gq G protein heterotrimeric that activates beta isoforms of phospholipase C
GTPase guanosine triphosphatase
GW627368X 4-(4,9-diethoxy-1,3-dihydro-1-oxo-2H-benz[f]isoindol-2-yl)
-N-(phenylsulfonyl)-benzeneacetamide
HETE hydroeicosateraenoic acids
HBV hepatitis B virus
HCC hepatocarcinoma
HO-1 heme oxygenase 1
Hypo-pRb1 underphosphorylated retinoblastoma 1
GRK2 G-protein-coupled receptor kinase 2
HPV human papillomavirus
IFNγ interferon gamma
IL-6 Interleukin 6
IL-1β Interleukin 1β
IP PGI2 receptor
IP6 inositol hexaphosphate
IS immune system
JNK c-Jun N-terminal kinase
Ki-67 nuclear protein related to cell proliferation
LKB1 hepatic kinase B1. Serine-threonine kinase that directly
phosphorylates and activates AMPK
LOX Lipoxygenase
LPS lipopolysaccharide
LPIAT1 lysophosphatidylinositol-acyltransferase 1
LTB Leukotriene B
LXA lipoxin A
MCL-1 cell differentiation protein from induced myeloid leukemia
MCF-7 Michigan Cancer Foundation-7 cell line
MDSC myeloid-derived suppressor cells
MHC-II major histocompatibility complex-II
miR-31-5p microRNA-31-5p
miR-574-5p microRNA-574-5p
M-MDSC immature monocytic derived suppressor cells
MMP cell matrix metalloprotease
MTII Melanotan II
mTOR muscular target of rapamycin
MYC myelocytomatosis and tumor transcription factor
NADPH Nicotinamide adenine dinucleotide phosphate
NFκB nuclear transcription factor kB
NK cells natural Killer cells
Cells 2021, 10, 1487 28 of 33

NO nitric oxide
NS-398 nifluric acid
NSAIDs nonsteroidal anti-inflammatory drugs
NSCLC non-small-cell lung carcinoma
PARP poly-ADP-ribose polymerase
Parthenolide NF-kB inhibitor
PD-L1 programmed death-ligand 1
PET positron emission tomography
pDC plasmacytoid dendritic cells
PG prostaglandin
PGD2 prostaglandin D2
PGDH 15-hydroxy-prostaglandin dehydrogenase
PGE1 prostaglandin E1
PGE2 prostaglandin E2
PGE3 prostaglandin E3
mPGES-1 microsomal PG synthetase 1
PGES-1 PG synthetase 1
PGF2a prostaglandin F-2α
PGF2β prostaglandin F-2β
PGI2 prostacyclin
PGIS prostacyclin synthetase
PGM PG urinary metabolite
PGT/SLCO2A1 PG transporter
PGH2 prostaglandin H2
PI3K phosphatidylinositol 3-kinase
PIP2 phosphatidylinositol 4,5-bisphosphate
PIP3 phosphatidylinositol (3,4,5)-trisphosphate
PKA-II protein kinase A type 2
PLC phospholipase C
PMN-MDSC granulocytic derived suppressor cells
PPARγ peroxisome proliferator-activated receptor
PSA PROSTATE ANTIGEN
PTEN FOSFATIDILINOSITOL-3,4,5-TRISFOSFATO 3-FOSFATASA
PTGER4 prostaglandin E receptor 4 [Homo sapiens (human)]
RGS10 Regulator of G-protein signaling 10
RHO Ras homologous GTPase protein
ROS reactive oxygen species
SC-236 4-[5-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide
SCLC small-cell lung carcinoma
Se selenium
sEH soluble enzyme epoxide hydrolase
Snail zinc finger transcriptional repressor
SND1 staphylococcal nuclease domain containing 1
SOX2 sex-determining region of Y chromosome (SRY)-related high-mobility-group box 2
SIK1/2 salt-inducible kinases 1/2
SRY sex-determining region of Y chromosome
STAT3 signal transducer and activator of transcription 3
TDO tryptophan 2,3-dioxygenase
TCF4 transcription factor 4
TMPRSS2 (Transmembrane protease, serine 2)
TNFα tumor necrosis factor Alpha
TNM stage classification of malignant tumors and the extent of spread of cancer
TPA tissue polypeptide antigen
TRAF2 TNF receptor associated factor 2
TRAIL TNF-related apoptosis-inducing ligand
TXA thromboxane A
TNF tumor necrosis factor
XRCC5 X-Ray Repair Cross Complementing 5
uPAR urokinase plasminogen activator surface receptor
Cells 2021, 10, 1487 29 of 33

UVB ultraviolet radiation B

VEGF vascular endothelium growth factor
YAP Yes1 associated transcriptional regulator
ZEB1 zinc finger E-box-binding homeobox 1
ZIP zinc Interacting Protein
ZBTB46 zinc finger and BTB Domain Containing 46
WNT wingless and Int-1

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