Vol.

61, No 4/2014
639–649
on-line at: www.actabp.pl
Review

Cyclooxygenase pathways
Jan Korbecki1, Irena Baranowska-Bosiacka1, Izabela Gutowska2 and Dariusz Chlubek1*
Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Szczecin, Poland; 2Department of Biochemistry and Hu-
1

man Nutrition, Pomeranian Medical University, Szczecin, Poland

This review compiles the current knowledge on the ef- TxA2. PGE2 is an important proinflammatory prostaglan-
fects of prostanoids — arachidonic acid metabolites — din revealing antiapoptotic properties, which plays essen-
on their own synthesis, activity and degradation. Interac- tial functions in renal physiology, the physiology of the
tion mechanisms between the receptors for the relevant immune system and is a developmental and growth fac-
compounds are presented, in particular with regard to tor associated with neoplasms (Harris, 2013). While PGF2α
the cooperation between a thromboxane A2 and prosta- is synthesized in the uterine wall and plays a crucial role
glandin I2 receptors. The questions of desensitization and not only in the physiology of this organ, it is also an au-
internalization of receptors are discussed. The stages of tocrine growth factor in connection with endometrial ad-
the inflammatory response and tumor progression are enocarcinoma (Sales et al., 2008; Woodward et al., 2011).
analyzed against the background of the disruption of A dehydrated derivative of PGD2 (15d-PGJ2) is a princi-
the synthesis of prostanoids. Special attention is given pal prostaglandin which inhibits prostanoid synthesis and
to the significance of 15-deoxy-Δ12,14-prostaglandin J2 the intensity of inflammatory reactions (Surh et al., 2011).
in the regulation of the synthesis of prostanoids and its Other important products of arachidonic acid transforma-
role as an anti-inflammatory agent. Ultimately, thera- tions include TxA2 and PGI2, synthesized by COX-1 and
peutic approaches as used in various treatments are dis- COX-2, respectively (Catella-Lawson et al., 1999). Both
cussed in the light of the available knowledge. these prostanoids play important roles in the physiology
and pathology of blood vessels (Caughey et al., 2001; De-
Key words: cyclooxygenase, prostaglandin, 15-deoxy-Δ12,14- bey et al., 2003; Meyer-Kirchrath et al., 2004). TxA2 causes
prostaglandin J2, receptor desensitization the aggregation of blood platelets and the contraction of
blood vessels, whereas PGI2 has opposite properties.
Received: 20 November, 2013; revised: 16 June, 2014; accepted:
06 September, 2014; available on-line: 23 October, 2014
PROSTANOID SYNTHESIS IN THE COURSE OF
INFLAMMATORY RESPONSE
BIOSYNTHESIS AND BIOLOGICAL IMPORTANCE OF Prostanoids play a chief role in inflammatory reac-
PROSTANOIDS tions. The synthesis of these compounds differs depend-
ing on the inflammatory reaction phase. During the first
Prostanoids are tissue hormones synthesized from long- hours after the activat on by a the proinflammatory sub-
chain polyunsaturated fatty acids, mainly arachidonic acid
(AA) (Sales et al., 2008). Phospholipase A2 (PLA2), and to *
be more precise cytoplasmic phospholipase A2 (cPLA2), e-mail: dchlubek@pum.edu.pl
is the first enzyme engaged in synthesizing these com- Abbreviations: 15-PGDH, 15-hydroxyprostaglandin dehydroge-
nase; 15d-PGJ2, 15-deoxy-Δ12,14-prostaglandin J2; AA, arachidonic
pounds, as it specifically releases AA from lipids in the acid; AC, adenylate cyclase; AP-1, activator protein 1; CaMK-II, Ca2+/
cell membrane, which then enters cyclooxygenase path- calmodulin-dependent protein kinase II; CBP, CREB-binding pro-
ways (Fig. 1) (Linkous & Yazlovitskaya; 2010). tein; COX, cyclooxygenase; COX-1, cyclooxygenase-1; COX-2, cy-
The two main COX isoforms are cyclooxygenase-1 clooxygenase-2; cPLA2, cytoplasmic phospholipase A2; CRE, cAMP
response element; CREB, cAMP response element-binding protein;
(COX-1) and cyclooxygenase-2 (COX-2). Both transform CRTH2, chemoattractant receptor-homologous molecule expressed
AA into prostaglandin H2 (PGH2), which then again on Th2 cells; DP, prostaglandin D2 receptor; EGFR, epidermal
transformed by proper synthases, mainly cytosolic pros- growth factor receptor; eNOS, endothelial nitric oxide synthase;
taglandin E synthase (cPGES), microsomal prostaglandin EP, prostaglandin E2 receptor; ERK1/2, extracellular-signal-regulated
kinases 1 and 2; FP, prostaglandin F2α receptor; GRK, G protein-cou-
E synthase-1 (mPGES-1), microsomal prostaglandin E pled receptor kinases; IKK, IκB kinase; IKKβ, IκB kinase subunit β;
synthase-2 (mPGES-2), prostaglandin I synthase (PGIS), IP, prostaglandin I2 receptor; IP3, inositol trisphosphate; JNK, c-Jun
and thromboxane synthase (TxS) into prostaglandins N-terminal kinase; KO, knockout; LPS, lipopolysaccharides; MAPK,
(PGs) and thromboxanes. mitogen-activated protein kinase; mPGES, microsomal prostaglan-
din E synthase; MRP4, multidrug resistance-associated protein 4;
The COX-1 gene is principally constitutive in function NF-κB, nuclear factor κB; NSAID, non-steroidal anti-inflammatory
and possesses a typical, GC-rich housekeeping promoter. drug; PG, prostaglandin; PGIS, prostaglandin I synthase; PGT, pros-
In contrast, the COX-2 gene resembles an early response taglandin transporter; PI3K, phosphatidylinositol-4,5-bisphosphate
gene. It is strongly induced by mitogenic and proinflam- 3-kinase; PKA, protein kinase A; PKB, protein kinase B; PKC, protein
kinase C; PLA2, phospholipase A2; PLCβ, phospholipase Cβ; PPARγ,
matory stimuli, superinduced by inhibitors of protein peroxisome proliferator-activated receptor γ; PTEN, phosphatidylin-
synthesis, and acutely regulated at both transcriptional ositol-3,4,5-trisphosphate 3-phosphatase; ROS, reactive oxygen
and posttranscriptional levels (Lasa et al., 2000). species; sPLA2, secreted phospholipase A2; TP, thromboxane A2 re-
The prostanoids of noteworthy biological significance ceptor; TPα, thromboxane A2 receptor α isoform; TPβ, thrombox-
ane A2 receptor β isoform; TxA2, thromboxane A2; TxS, thrombox-
include: prostaglandin E2 (PGE2), prostaglandin F2α ane synthase.
(PGF2α), prostaglandin D2 (PGD2), 15d-PGJ2, PGI2, and
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J. Korbecki and others 2014

The pathways of prostanoid synthesis tend to become

dysregulated with the progression of a neoplastic dis-
ease (Table 1). First of all, the expression of COX-2 and
mPGES-1 is increased and consequently the intensity of
PGE2 production increased (Badawi & Badr, 2003; Na-
kanishi et al., 2008). Apart from the amplifying inflam-
matory reactions, the anti-inflammatory mechanisms are
dysregulated. Expression of peroxisome proliferator-acti-
vated receptor γ (PPARγ), which participates in the inhi-
bition of inflammatory reactions, is decreased due to an
increased COX-2 expression (Inoule et al., 2000). Also
the synthesis of 15d-PGJ2 decreases as a result of the
rise in mPGES-1 expression (Badawi & Badr, 2003). The
expression of mPGES-1 causes an increased PGE2 syn-
thesis, as mentioned above, at the cost of PGD2, which
leads not only to the deactivation of the function of
15d-PGJ2, but also supports angiogenesis and the pro-
gress of neoplastic diseases (Murata et al., 2011; Davoine
et al., 2013).
The changes in the prostanoid synthesis in neoplastic
cells occur along with changes in the enzymes degrad-
ing those compounds. Neoplastic cells reveal an entire
lack or a decreased expression of 15-hydroxyprostaglan-
din dehydrogenase (15-PGDH), a PGE2 degrading en-
zyme (Wolf et al., 2006; Jang et al., 2008; Lee et al., 2013).
The mechanism underlying the expression disorders of
15-PGDH may partially result from the increased expres-
sion of COX-2 (Tong et al., 2006). In colorectal neopla-
Figure. 1. COX pathways.
sia a lowered expression of the prostaglandin transporter
Arachidonic acid is released from cell membrane by cPLA2. In can (PGT) participating in uptaking PGs is often noted, as
then undergo transformations by cytochrome P450, lipoxygenases well as an increased expression of multidrug resistance-
or COX. The latter enzymes transform arachidonic acid into PGH2. associated protein 4 (MRP4) taking part in the secretion
The newly formed prostaglandin is transformed into other prosta- of PGs from the cell (Holla et al., 2008). Furthermore,
glandins or TxA2 by appropriate synthases.
the expression of prostaglandin receptors also increases.
stance COX-2 expression increases and cPLA2 is activat- An increased expression of prostaglandin E2 receptor-4
ed, which leads to increased PGH2 synthesis (Murakami (EP4) has been observed, among others, on colorectal
et al., 1997). However, a simultaneous lack of mPGES-1 neoplastic cells (Chell et al., 2006). All these changes re-
expression, transforming PGH2 into PGE2, results in a sult in an increased concentration of PGE2 in the sur-
coincident increase of PGD2 synthesis (Xiao et al., 2012). roundings of neoplastic cells. This causes an autocrine
Nonetheless, the COX-2 expression in this phase does activation of neoplastic development and the progress of
not depend on the autocrine activation by PGE2 (Mu- the disease.
rakami et al., 1997).
During the second phase, lasting for 12 to 48 hours INFLAMMATORY REACTION POSITIVE FEEDBACK LOOP
after the stimulation, mPGES-1 and cPLA2 expres- INVOLVING PROSTAGLANDIN E2
sion takes place, which intensifies PGE2 synthesis (Mu-
rakami et al., 1997; Xiao et al., 2012) with an unchanged COX-2 expression is in a positive feedback loop with
synthesis of PGD2 (Xiao et al., 2012). Expression of its products a PGE2 and PGF2α (Inoule et al., 2000; Sales
COX-2 and cPLA2 undergoes autocrine stimulation by et al., 2001; 2008). This process is of considerable signif-
PGE2, but there is no simultaneous influence of this icance as far as autocrine support of inflammatory reac-
compound on the expression of mPGES-1 (Murakami tions and activation of neoplastic cells’ growth (Sales et
et al., 1997; Xiao et al., 2012). The addition of inhibi- al., 2001; 2008). The mechanism associated with the way
tors of COX-2 and/or cPLA2 results in a simultaneously prostaglandins influence COX-2 expression consists in
decreased expression of both enzymes (Murakami et al., increasing the COX-2 mRNA stability and in activating
1997; Xiao et al., 2012), while adding PGE2 suppresses the COX-2 gene promoter (Sales et al., 2008). Both these
the effect of these inhibitors on the COX-2 and cPLA2 processes depend on the type of cells (Inoule et al., 2000;
expression (Murakami et al., 1997). Besides, in the course Sales et al., 2001; 2008).
of this inflammatory phase, depending on its duration, PGE2 increases the expression of COX-2 acting
the expression of COX-2 can be hampered by 15d-PGJ2 through its receptors, prostaglandin E2 receptor-2 (EP2)
(Inoue et al., 2000). and EP4, which activate adenylate cyclase (AC), and this
increases the concentration of cAMP in the cell (Saku-
DYSREGULATION OF THE PROSTANOID SYNTHESIS ma et al., 2004). In turn, cAMP increases the stability of
PATHWAY IN NEOPLASTIC DISEASES COX-2 mRNA and activates COX-2 promoter by means
of protein kinase A (PKA) and cAMP response ele-
PGE2 plays an important role in cancer develop- ment-binding protein (CREB) (Inoule et al., 2000; Sales
ment. It shows antiapoptotic activity and supports et al., 2001; Fujino et al., 2005; Díaz-Muñoz et al., 2012).
angiogenesis, which is why it could be a promising Activated EP4 also activates phosphatidylinositol-4,5-bi-
target in an antineoplastic therapy (Greenhough et al., sphosphate 3-kinase (PI3K), which causes a PKA-inde-
2009). pendent signal transduction to CREB (Fujino et al., 2005).
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Cyclooxygenase pathways 641

Table 1. Prostanoid pathway compounds under three conditions.

Comparison of three conditions: normal condition, inflammation caused by a pro-inflammatory factor, and cancer
Trait Normal condition Inflammation Cancer cell
COX-2 protein expression none present present
mPGES-1 protein expression none present present
PGE2 level low high high
15-PGDH protein expression high low none
PGD2 level normal high low
15d-PGJ2 level normal high low

PGE2 also increases COX-2 expression by activating mi- An activated prostaglandin F2α receptor (FP) reduces
togen-activated protein kinase (MAPK) cascades (Faour the PGT activity, and hence the uptake of prostaglandin
et al., 2001; Rösch et al., 2005). EP4 uses PI3K to activate through this transporter is reduced (Vezza et al., 2001).
the extracellular-signal-regulated kinases 1 and 2 (ERK1/2) This regulation occurs through the Gs protein, but is in-
MAPK cascade, leading to increased COX-2 expression dependent of AC (Vezza et al., 2001). Additionally, the
(Fujino et al., 2003; 2005; Mendez & LaPointe, 2005; Rösch levels of COX-2 and 15-PGDH expressions are directly
et al., 2005; Sales et al., 2008). Protein kinase C (PKC) and related to each other. Increased expression of one en-
Ca2+ can also participate in the activity of PGE2 (Rösch et zyme inhibits the expression of the other one (Tong et
al., 2005). The additionally activated EP4 receptor, through al., 2006; Liu et al., 2008). Nevertheless, the dependence
a pathway independent of PKA, activates the p38/MAP- between the expression of both enzymes is independ-
KAPK-2/hsp 27 cascade which is responsible for increas- ent of their activity. Adding an inhibitor of one enzyme
ing the stability of COX-2 mRNA (Lasa et al., 2000; Faour does not affect the expression of the other (Tong et
et al., 2001; Rösch et al., 2005). The stability of COX-2 al., 2006). The mechanism interconnecting the levels of
mRNA is enhanced by preventing its degradation from the COX-2 and 15-PGDH expression remains unclear. Most
3’-untranslated region of mRNA rich in AU nucleotides probably 15-PGDH is capable of binding 3’-untranslated
(Lasa et al., 2000; Faour et al., 2001). region of mRNA COX-2 and, thereby destabilizing it
(Tong et al., 2006). The reciprocal influence of COX-2
on 15-PGDH expression, is even less well understood
DEGRADATION PATHWAY OF PROSTAGLANDIN E2
and is still being that examined in order to understand
the regulation of expression of these enzymes in neo-
After synthesis PGE2, is secreted outside the cell by plastic cells, where COX-2 overexpression and reduced
MRP4. During the following phase, it can be uptaken 15-PGDH expression is observed.
by PGT and degraded in the cytoplasm (Fig. 2) (Vez-
za et al., 2001). This particular transporter specifically
transports not only PGE2, but also PGD2 and PGF2α MECHANISMS OF PROSTAGLANDIN F2α-INDUCED
(Vezza et al., 2001). This is followed by the degradation CYCLOOXYGENASE-2 EXPRESSION
of PGE2 in the cytoplasm by 15-PGDH into an inac-
tive 15-keto-PGE2 form (Holla et al., 2008). Products of PGF2α is yet another prostanoid with a crucial role in
COX transformations take part in regulating the PGE2 the regulation of the synthesis of the prostanoids dis-
degradation pathway. cussed in this review. It increases the expression of
COX-2 through its receptor (FP) and hence increases its
own synthesis (Sales et al., 2008). The autocrine activation
of this enzyme’s expression by PGF2α is of considerable
importance for the growth and development of endo-
metrial adenocarcinoma. When present in concentrations
reaching 100 nM PGF2α may even activate EP2 (Fig. 3),
leading to the same signal transduction as that caused by
PGE2 (Sales et al., 2008). FP activates phospholipase Cβ
(PLCβ) which releases inositol trisphosphate (IP3) and
diacylglycerol (Sales et al., 2008; Woodward et al., 2011)
which activate PKC, however, this pathway will not in-
duce the expression of COX-2 protein (Sales et al., 2008).
PGF2α binds to FP, that caused signal transduction, which
activates ERK1/2 MAPK and hence results in COX-2 ex-
pression (Jabbour et al., 2005; Sales et al., 2008).
Whilst PLCβ activates ERK1/2 MAPK by means
of epidermal growth factor receptor (EGFR), which
Figure 2. PGE2 degradation.
PGE2 is secreted from cells by MRP4. Outside the cells, PGE2 ac- leads to expression of COX-2 (Sales et al., 2004; 2008),
tivates its receptors EP2 and EP4, thus increasing COX-2 expres- it seems that also PKA also participates in transduc-
sion. It may also undergo uptake by means of PGT in the cyto- ing signals from FP to ERK1/2 MAPK (Sales et al.,
plasm, PGE2 is degraded by 15-PGDH to 15-keto-PGE2. COX-2 and 2008). As for EGFR activation, c-Src and metallopro-
15-PGDH, the key enzymes in the synthesis and degradation of
PGE2, mutually inhibit each other’s their expression, an increase teinases may also participate in this process (Sales et al.,
in the expression of one enzyme leads to reduced expression of 2005). It has also been shown that the upregulation of
the other. COX-2 expression results from activating CREB and ac-
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J. Korbecki and others 2014

the pace of neoplastic growth and development (Surh et

al., 2011). It is formed by non-enzymatic dehydration of
PGD2 (Surh et al., 2011).
By means of their receptors, respectively EP2 and EP4,
as well as the prostaglandin D2 receptor (DP), PGE2
and PGD2 increase the cAMP concentration and thereby
enhance the expression of COX-2 protein (Sakuma et
al., 2003). After a certain period of time, however free
PGD2 becomes dehydrated to 15d-PGJ2, which in low
concentrations reduces the expression of COX-2 protein
(Surh et al., 2011) through a pathway that can be de-
pendent or independent on the PPARγ receptor (Fig. 4)
(Inoule et al., 2000; Sawano et al., 2002). In cells treated
with a proinflammatory factor, the activated PPARγ re-
ceptor disturbs the induction of COX-2 protein expres-
sion along various routes. In particular, it disturbs the
activation of nuclear factor κB (NF-κB) (Inoule et al.,
2000). Additionally, PPARγ disrupts the activation of the
AP-1 transcription factor by means of c-Jun N-terminal
kinase (JNK) MAPK and binds, and thereby inactivates,
CREB-binding protein (CBP)/p300 (Subbaramaiah et al.,
2001). It has also been shown that 15d-PGJ2 inhibits sig-
nal transduction through ERK1/2 and JNK MAPK into
AP-1, along a pathway independent of PPARγ receptor
(Sawano et al., 2002). Additionally, 15d-PGJ2 inhibits the
activation of NF-κB by restraining the activity of IκB
kinase subunit β (IKKβ) by modifying its cysteine resi-
dues (Boyault et al., 2004). The disrupted phosphoryla-
Figure 3. Mechanism of COX-2 expression stimulation by PGE2 tion precludes the degradation of the NF-κB inhibitor:
and PGF2α. IκBα (Boyault et al., 2004). Apart from that, 15d-PGJ2
Both prostaglandins activate their respective receptors: EP2, EP4 modifies cysteine residues in the DNA binding domain
and FP. At larger levels of the order of 100 nM, PGE2 is also capa- on p65 NF-κB, which leads to its inactivation (Straus et
ble of activating the FP receptor. EP2 and EP4 cause activation of
AC and transduction of the signal to PKA. At the same time, FP ac- al., 2000; Boyault et al., 2004).
tivates PLCβ, products of which are involved in activation of PKC The molecular mechanism of the modification of
causing influx of calcium ions. This may have a synergistic effect cysteine residues by 15d-PGJ2 is well known. The ar-
in the EP2 and EP4-mediated activation of AC. Eventually, the sig- rangement of atoms in the 15d-PGJ2 ring creates an
nal is transducted to ERK1/2 MAPK, leading to activation of COX-2
promoter by CREB and AP-1.

tivator protein 1 (AP-1) by means of ERK1/2 MAPK

(Sales et al., 2008).
The affinity of PGE2 for FP is lower (119 nM) than
its affinity for EP2 (4.9 nM) or EP4 (0.79 nM) (Abra-
movitz et al., 2000). In concentrations reaching 100nM,
PGE2 increases the expression of COX-2 not only by its
EP2 and EP4 receptors, but also through FP (Sales et al.,
2008). When increasing the expression of COX-2, acti-
vated EP and FP receptors act synergistically, as they ac-
tivate ERK1/2 MAPK through PKA (Sales et al., 2008).
The calcium influx, dependent on IP3, activates Ca2+/
calmodulin-dependent protein kinase II (CaMK-II) and
ultimately the transmission of signal to Ca2+ dependent
AC isoform 3 (Abera et al., 2010). The cross-activation
of EP and FP receptor by PGE2 and PGF2α is crucial in
neoplastic cells expressing FP as in endometrial adeno-
carcinoma (Sales et al., 2008; Woodward et al., 2011). The
both prostaglandins increase COX-2 expression, which
results in an autocrine upregulation of their level. This,
again, leads to the development and growth of the neo-
plasm (Sales et al., 2005; 2008).

15-DEOXY-Δ12,14-PROSTAGLANDIN J2 AS AN ANTI-
INFLAMMATORY REGULATOR OF PROSTANOID Figure 4. Effects of 15d-PGJ2 on COX-2 expression.
15d-PGJ2 undergoes cytoplasmic uptake and activates its receptor
SYNTHESIS PPARγ. This leads to inhibition of the activity of NF-κB, JNK MAPK
and CBP/p300. Another pathway of 15d-PGJ2 activity is direct inhi-
Apart from the above-mentioned PGE2 and PGF2α, bition of p65 NF-κB and IKKβ. Both pathways decrease COX-2 pro-
other prostaglandins also exert an autocrine influence on tein expression. At very large levels, 15d-PGJ2 deactivates antioxi-
dants containing free –SH groups. By this mechanism, it sensitizes
prostanoid synthesis. 15d-PGJ2 is a prostanoid regulat- the cells to the effects of ROS, which may lead to an increase in
ing the intensity of inflammatory reactions and reducing COX-2 protein expression.
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Cyclooxygenase pathways 643

Table 2. Properties of the prostanoids receptors.

The receptors are categorized by their ligands and activated pathways. The main activated enzymes are AC or PLC. Receptors are desensis-
tized or internalized following phosphorylation by PKC, PKA and GRK.

Receptor Ligand Main activation effect PKA activation PKC activation Receptor desensitization/internalization pathway

EP1 PGE2 PLC, ↑Ca2+, no IP3 – + PKC

EP2 PGE2 AC, ↑cAMP + – Not affected

EP3 PGE2 AC, ↓cAMP – – GRK(EP3α)

EP4 PGE2 AC, ↑cAMP, PI3K + – GRK, PKC*

DP PGD2 AC, ↑cAMP, ↑Ca2+ + – PKC*, GRK

CRTH2 PGD2 AC, ↓cAMP, ↑Ca2+ – + PKC, PKA*, GRK

IP PGI2 AC, ↑cAMP, PLC + + PKC, PKA(AC isoform 5 and 6)

FP PGF2α PLC, ↑Ca2+ – + PKC(FPA), constitutive FPB,

TP TxA2 PLC, ↑Ca2+ – + GRK, PKA(TPα)*, PKC

*cross-desensitization/internalization pathway triggered by an other type of receptor

electrophilic carbon (Straus et al., 2000) which undergoes tive stress and second messengers, such as ROS (Shibata
Michael addition with cysteine residues (R-SH) (Straus et al., 2003; Kim et al., 2008). This effect may be relieved
et al., 2000). The reaction with cysteines in the catalytic by increasing the concentration of antioxidants with free
centre, can lead to the inactivation of an enzyme, such R-SH groups which react directly with 15d-PGJ2 (Kim et
as IKKβ. As a consequence, this evokes the reduction of al., 2008).
COX-2 protein expression. The regulation of COX-2 expression is a dynamic pro-
Moreover, 15d-PGJ2 affects the expression of cess. On one hand it is inhibited by the PGD2 metabolite
COX-2 through mechanisms related to the synthesis of 15d-PGJ2, while on the other it is activated by PGE2. The
reactive oxygen species (ROS), since at low concentra- two prostanoids, 15d-PGJ2 and PGE2, form a more com-
tions 15d-PGJ2 activates cellular defense mechanisms plex system of interdependencies. Following the treatment
against ROS and at the same time increases the concen- of cells with an inflammatory factor, such as lipopolysac-
tration of antioxidants, e. g., glutathione (Koppal et al., charides (LPS), the level of PPARγ is reduced, which leads
2000). It also increases the level of heme oxygenase 1 to partial deactivation of 15d-PGJ2 and simultaneously to
expression (Koppal et al., 2000). An increased level of increased expression of COX-2 (Inoule et al., 2000). Con-
antioxidants in the cell disrupts signal transduction along versely, blocking the activity of mPGES-1, an enzyme col-
pathways where ROS function as second messengers. laborating with COX-2 in the reduction of PGE2, increas-
This disturbes transduction of NF-κB activation signals es expression of PPARγ (Kapoor et al., 2007). This effect
and activation of MAPK kinase cascades responsible for is caused by signal transduction from the PGE2 receptor
COX-2 expression (Koppal et al., 2000). to PI3K and PKB, which in turn inhibit the expression of
Paradoxically, at high concentrations 15d-PGJ2 may PPARγ (Kapoor et al., 2007).
actually increase the expression of COX-2. In breast
cancer cells, 30 μM 15d-PGJ2, increases the expression LIGAND-MEDIATED DESENSITIZATION AND
of COX-2 by inhibiting the activity of phosphatidylin- INTERNALIZATION OF RECEPTORS
ositol-3,4,5-trisphosphate 3-phosphatase (PTEN) (Kim
et al., 2008). This causes the activation of protein kinase Desensitization means reducing the sensitivity of a re-
B (PKB) and, signal transduction upregulating COX-2 ceptor in response to a prolonged exposure to a given
expression (Kim et al., 2008). 15d-PGJ2 can also acti- ligand. This process plays an important role in the physi-
vate p38 MAPK and, by means of EGFR, also of the ology of receptors, especially when reducing the cellular
ERK1/2 MAPK cascade, which leads to the induction response to a particular factor, which may become too
of mRNA COX-2 synthesis and also increases its sta- intense.
bility (Kitz et al., 2011). This mechanism resembles the Exposure to PGE2 results in internalization and de-
route by which COX-2 expression is induced by ROS. sensitization of EP4 receptor, whilst EP2 maintains its
15d-PGJ2 and ROS reveal a similar activity in re- sensitivity towards PGE2 (Table 2) (Desai et al., 2000).
lation to enzymes, by modifying cysteine residues in The C-tail plays a key role in desensitization of EP4,
their catalytic centres. ROS create disulphide bonds or as it is phosphorylated by G protein-coupled receptor
sulfenic acid (Cys-SOH), which often inhibits the activ- kinases (GRK) (Desai et al., 2000; Slipetz et al., 2001).
ity of enzymes with a cysteine in their catalytic centre Throughout this process, PKA does not exert any influ-
(Meng & Zhang, 2013). When 15d-PGJ2 reacts with a ence on the EP4 (Neuschäfer-Rube et al., 1999; Slipetz et
cysteine residue, it also inhibits the activity of enzymes al., 2001). PKC is able to influence EP4, but this kinase
(Straus et al., 2000; Boyault et al., 2004). This is why the is not activated by EP4 receptor (Neuschäfer-Rube et al.,
both compounds can have similar effects when present 1999; Slipetz et al., 2001). As far as the rat prostaglan-
at high concentrations. Additionally, 15d-PGJ2 inactivates din E2 receptor-3 (EP3) is concerned, EP3α undergoes
glutathione and thioredoxin, sensitizing the cell to oxida- desensitization by phosphorylation dependent on GRK,
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J. Korbecki and others 2014

whereas EP3β does not (Neuschäfer-Rube et al., 2005). Zhang et al., 2002; Bosetti et al., 2004; Choi et al., 2006;
Prostaglandin E2 receptor-1 (EP1) undergoes desensitiza- Sandee et al., 2009). COX-2 KO cells do not respon to
tion and internalization following of phosphorylation by proinflammatory factors (Kirtikara et al., 1998). In the
PKC (Katoh et al., 1995). mouse brain with a COX-2 knockout it a decreased con-
Aside from EP, other receptors also undergo desen- centration of PGE2 is observed due to a non fully com-
sitization and internalization. Receptors for PGF2α are pensating increased COX-1 protein expression (Bosetti
present in two isoforms: FPA and FPB. PGF2α causes in- et al., 2004). In macrophages, the COX-2 defect causes
ternalization of FPA dependent on PKC, while FPB un- an increase in the expression of 5-lipoxygenase (Zhang et
dergoes partial, constitutive internalization independent al., 2002; Bosetti et al., 2004).
of the ligand, since there are no phosphorylation sites Due to the production of TxA2 by COX-1, the lack of
for PKC in its C-tail (Srinivasan et al., 2002). this enzyme decreases the level of this eicosanoid as well
PGD2 has two receptors: DP and chemoattractant as the level of TxS expression (Choi et al., 2006). On the
receptor-homologous molecule expressed on Th2 cells other hand, expression of COX-2 and synthesis of PGE2
(CRTH2). Both these receptors have a C-tail susceptible occurring under the influence of a proinflammatory fac-
to phosphorylation, which is essential for their internali- tor in COX-1 KO mice was higher when compared with
zation (Gallant et al., 2007; Schröder et al., 2009; Roy et wild-type cells (Kirtikara et al., 1998).
al., 2010). CRTH2 undergoes the internalization through In brains of COX-1 KO mice the PGE2 synthesis in-
phosphorylation with PKC and a GRK: GRK2, GRK5 creases, as does COX-2 expression, which is caused by
and/or GRK6 (Roy et al., 2010). DP internalization de- the activation of NF-κB (Kanekura et al., 2002; Choi
pends on PKC, but this kinase is not activated by DP et al., 2006). This activation is due to an increased ex-
(Gallant et al., 2007). What is more, DP internalization pression of NF-κB (subunits p50 and p65) and next
depends only on GRK2 and not depend on GRK5 or to constant activation of IκB kinase (IKK) (Choi et
GRK6 (Gallant et al., 2007). Another difference between al., 2006). In contrast in COX2-KO animals, the basal
these two receptors lies in the fact that the internaliza- level of NF-κB activaty is decreased (Rao et al., 2005).
tion of CRTH2 depends on the activation of PKA (Gal- In brain cells with COX2 KO the PGE2 concentration
lant et al., 2007). However, when this kinase is activated is decreased, which may lead to reduced activation of
but CRTH2 is not, it does not result in the internaliza- NF-κB (Poligone & Baldwin, 2001; Rao et al., 2005; Choi
tion of the receptor (Gallant et al., 2007). The internali- et al., 2006). Nevertheless, the exact mechanisms underly-
zation of the receptors for PGD2 also depends on arres- ing the interdependence of COX-1 and COX-2 expres-
tins: that of DP on arrestin-2 and -3, and of CRTH2 on sions require a more thorough research. It seems that
arrestin-3 only (Gallant et al., 2007; Schröder et al., 2009; the both enzymes inhibit their own expressions, and the
Roy et al., 2010). lack of one causes a compensating increase in the ex-
pression of the second. Probably the expression of one
COX isoform depends on the presence of mRNA or the
PROSTAGLANDIN SYNTHESIS COMPENSATION IN
protein of the other isoform. Another possibility is that
CELLS WITH DISTURBED OF CYCLOOXYGENASE
products of COX pathways affect the expression of the
PATHWAYS
other COX isoform.
Due to the pro-neoplastic character of the products
Gene knockout (KO) can serve as a model for the of AA transformations by COXs and lipoxygenases, re-
chronic use of COX inhibitors. Dysruption of either cent studies focus on the mechanisms of the inhibition
COX gene, COX-1 or COX-2, upregulates PGE2 syn- of expression and activity of cPLA2α. In the course of
thesis in cultured cells (Table 3) (Kirtikara et al., 1998; inflammatory reactions, this enzyme releases AA from
Kanekura et al., 2002). Cells with COX-1 or COX-2 de- cell membranes lipids. Inhibiting the cPLA2α activity si-
fects show an increased expression of cPLA2, secreted multaneously inhibits the activity of COX and lipoxyge-
phospholipase A2 (sPLA2), mPGES-1, as well as the sec- nases. In mouse brain, cPLA2α KO leads to a reduction
ond, functional COX isoform, but they also exibit by a in COX-2 expression, which then effects in lower PGE2
decreased expression of mPGES-2 (Kirtikara et al., 1998;
synthesis, while the expression of COX-1 and 5-lipoxy-
genase is unaffected (Bosetti & Weerasinghe, 2003; Sa-
Table 3. Prostanoid synthesis in COX KO cells. pirstein et al., 2005). A decreased COX-2 expression may
COX KO cells are characterized by increased production of PGE2, result from the inhibition of platelet-activating factor
expression of phospholipase A2 and of the other COX isoform. (PAF) synthesis (Serou et al., 1999; Bosetti & Weeras-
Trait COX-1 KO COX-2 KO inghe, 2003). PAF activates p38 and ERK1/2 MAPK,
which increase the expression of COX-2 (Serou et al.,
PGE2 production ↑ ↑ 1999). The expression of COX-2 is induced throught the
proinflammatory factor. In mice with cPLA2α defect, the
cPLA2 expression ↑ ↑
expression of COX-1 decreases after proinflammantory
sPLA2 expression ↑ ↑ factor treatment, while the induction of COX-2 expres-
sion and production of PGE2 are disturbed (Sapirstein et
COX-1 expression ↑ al., 2005). In contrast in prostate cancer models block-
↑
ing the cPLA2α activity leads to increased expression
COX-2 expression
of COX-1 and PGE2 production, with no changes in
In brain
COX-2 expression. Additionally, the secretion of li-
poxygenase transformation products is reduced. Add-
PGE2 concentration ↑ ↓ ing 5- and/or 12-hydroxyeicosatetraenoic acid, products
of lipoxygenases transformations, reduced the level of
mPGES-2 expression ↓ ↓ COX-1 expression and PGE2 production (Niknami et al.,
2010).
NF-κB activation ↑ ↓ Inhibiting the activity of mPGES-1, an enzyme en-
gaged in the production of PGE2 dependent on COX-
Vol. 61
Cyclooxygenase pathways 645

2, could be used as a therapeutic strategy in neoplasms. depend on the type cell as well as the domination of
mPGES-1 KO disturbes the synthesis of PGE2 and oth- the described isoforms of the receptor (Miyosawa et al.,
er products of COXs pathways. Enzymatic defects in 2006). Most probably the activation of TPα leads to a
mPGES-1, reducing in the production of PGE2 may be minimally increased cAMP concentration to the activa-
organ specific, e.g.,. they may concern solely the brain tion of PKA, whereas the second isoform TPβ has an
or the stomach. Simultaneosly the production of PGI2, entirely opposite influence on AC (Hirata et al., 1996).
TxA2 and PGD2 in the digestive system is increased TPα activates ERK1/2 MAPK within several minutes
(Boulet et al., 2004; Elander et al., 2008). after TxA2 binding, which is then followed by the de-
During the stimulation of the inflammatory reaction activation of this cascade of kinases (Miggin & Kinsella,
in mPGES-1-KO mice the synthesis of TxA2, PGI2, 2002b; Miyosawa et al., 2006). While the other isoform,
PGF2α and PGD2 is increased, as is the expression of TPβ, activates ERK1/2 MAPK after a similar period of
COX-2, when compared to cells with functional mPG- time, this is a long-lasting process, since an hour later
ES-1 (Boulet et al., 2004; Trebino et al., 2005; Brenneis the phosphorylation of ERK1/2 MAPK is still present
et al., 2008; Elander et al., 2008), most likely to compen- (Miggin & Kinsella, 2002b; Miyosawa et al., 2006).
sate for the diminished level of PGE2. The compensa-
tory mechanisms is probably not connected with changes INTERACTIONS BETWEEN THROMBOXANE A2 AND
in the expression of particular synthases, but rather with PROSTAGLANDIN I2 RECEPTORS
the availability of PGH2 (Boulet et al., 2004). Since there
is no mPGES-1 expression, PGH2 is available for trans- The dimerization or oligomerization of receptors plays
formation to proper prostanoids by other synthases. Ap- an important role in transmitting signals from TP or IP.
plication of mPGES-1 inhibitors in neoplastic therapy in It does not result in proper signal transduction, but can
order to limit the synthesis of PGE2 can thus cause an modulate the properties not only of the receptors, but
increased synthesis of other proneoplastic prostanoids,
and as a consequence lead to effects contrary to those also of the signals they transmit (Wilson et al., 2004).
Expression of both TP isoforms can lead to the for-
intended (Elander et al., 2008). mation of their heterodimer. It probably takes place im-
mediately after the receptors are synthesized and can
THE IMPACT OF THROMBOXANE A2 AND later cause a reduction of TPα expression (Sasaki et al.,
PROSTAGLANDIN I2 ON PROSTANOID SYNTHESIS 2006). The TP heterodimer differs from the homodi-
PATHWAY mers, because it produces a stronger signal in response
to certain agonists (Wilson et al., 2007b). Nevertheless,
TxA2 and PGI2 increase COX-2 expression, which it is a simplified model, since it seems that TP receptors
leads to increased PGI2 synthesis in blood vessels. Upon form both hetero- and homodimers, their oligomeriza-
PGI2 binding, prostaglandin I2 receptor (IP) upregulates tion does not depend on the presence of a ligand (Laro-
cAMP synthesis, which induces COX-2 expression in the che et al., 2005). Individual receptors in an oligomer are
smooth muscles of blood vessels (Debey et al., 2003; Sa- connected with each other by disulphide bonds, which
kuma et al., 2003; Meyer-Kirchrath et al., 2004). Increased can be split only by reducting factors (Laroche et al.,
expression of cAMP inducible early repressor occurs 2005).
along with the increased COX-2 expression (Debey et Apart from the fact that these two TP isoforms in-
al., 2003). This transcriptional repressor binds cAMP re- teract with and affect each other, they can also interact
sponse element-binding protein (CREB), and decreases with IP. The receptors dimerization (TP and IP) and sig-
the expression of genes including COX-2 (Debey et al., nal transduction takes place after the activation of these
2003). receptors. An activated TPα can dimerize with a nonin-
TxA2 affects the expression of COX-2 by a different
mechanism. Due to its instability, TxA2 functions only
locally (Miyosawa et al., 2006). TxA2 binding to throm-
boxane A2 receptor (TP) activates PLCβ without affrct-
ing cAMP concentration. (Sakuma et al., 2003; Wood-
ward et al., 2011). PLCβ causes the induction of COX-2
expression through ERK1/2 MAPK and thus increases
the synthesis of PGE2 and PGI2 in blood vessel cells
(Caughey et al., 2001; Chu et al., 2003). The activation of
ERK1/2 MAPK through ligand-activated TP is complex
process involving PKC, PKA and PI3K (Miggin & Kin-
sella, 2002b).
Expression of COX-2 and synthesis of PGI2 can sup-
press the activity of TxA2 in prolonged exposure to this
thromboxane. The detailed mechanism associated with
activating the expression of COX-2 is very well known.
One can distinguish two isoforms of receptors for TxA2:
thromboxane A2 receptor isoform α (TPα) and β (TPβ).
The difference between these two receptors is associ-
ated with their C-tail located at the cytoplasmic side of
the cell membrane (Miyosawa et al., 2006). The two iso- Figure 5. Dependence between IP and TPα.
The two receptors activate different signalling pathways. IP in-
forms of TP can be associated with diferent G proteins creases cytoplasmic cAMP level by activating AC while TPα acti-
and can therefore activate the MAPK cascade in differ- vates PLC and AC in IP/TPα heterodimer. Both receptors act syner-
ent manners. Among others, PKA participates in the gistically upon AC activation. This is probably due to heterodimer-
activation of ERK1/2 MAPK by TPα, but not by TPβ ization which alters the signalling pathway activated by TPα. TPα
is desensitized by GRK. In addition, ligand-activated IP triggers the
(Miyosawa et al., 2006). The signal transduction pathways same process in TPα by means of PKA.
646
J. Korbecki and others 2014

activated IP and hence transmit a signal similar to that

of an activated IP receptor, which means that it causes
an increased cAMP concentration (Fig. 5) (Wilson et al.,
2004). Yet this process is much more intensified than
the sole activity of TPα (Hirata et al., 1996; Wilson et al.,
2004). What is more, the activation of both receptors in
the IP with TPα-dimer causes a synergistic activation of
AC, producing a considerably higher cAMP concentra-
tion than IP ialone (Wilson et al., 2004). The cooperation
between the two receptors could be of significance as
far as the activity of PGI2 is concerned, as it will sup-
press the influence exerted by TxA2 when both these
prostanoids are simultaneously present a in blood vessel
(Wilson et al., 2004).
Apart from the influence exerted by IP on TP, EP3
can also increase the intensity of signal transduction
Figure 6. TP desensitization mechanism.
from TP. This effect most probably depends on the TPα is desensitized by PKC and/or GRK. The activity of GRK to-
formation of TP oligomers with EP3 (Reid & Kinsella, wards TPα depends on receptor activation of eNOS. The activity of
2009). TPα may also be affected by activation of other prostaglandin re-
ceptors that exert their action on TPα via PKC or PKA. PKA has no
effect on the ligand sensitivity of TPβ. PKC and GRK are involved
DESENSITIZATION OF RECEPTORS FOR THROMBOXANE only in this process. However, GRK-mediated phoshorylation of
A2 AND PROSTAGLANDIN I2 TPβ is independent of eNOS.

The desensitization of receptors for TxA2 and PGI2 is synthesis and the recirculation of old receptors, leading
of considerable importance in chronic exposure of cells to a net diminution of IP level (Nilius et al., 2000).
to a large concentration of a certain prostanoid. Iloprost, The receptor for TxA2 undergoes desensitization
a PGI2 homologue, is capable of desensitizing the IP re- following phosphorylation by GRK and partially by
ceptor, leading to its internalization (Nilius et al., 2000). PKC (Fig. 6) (Flannery & Spurney, 2002). It is a com-
In addition to activating AC, IP also activates PLC, plex process. TPα undergoes phosphorylation by PKC
which again leads to transduction of signals to PKC and GRK, and in turn the activity of GRK depends
(Kam et al., 2001). This could be due to the fact that on the activation of endothelial nitric oxide synthase
iloprost acts not only on IP itself, but also has a similar (eNOS) by this receptor and on the transmission of
affinity towards EP1 (Abramovitz et al., 2000; Schermuly signals to guanylate cyclase (Kelley-Hickie et al., 2007).
et al., 2007). Another possibility is that PLC is activated Activated TPβ undergoes desensitization as well, but
by IP. Upon phosphorylation of murine IP by PKA, the here mainly GRK2 and GRK3 carry outwith little in-
receptor becomes coupled to Gq and Gi (Lawler et al., volment of the phosphorylation with PKC (Kelley-
2001; Miggin & Kinsella, 2002a). In contrast, human IP Hickie & Kinsella, 2006). After the phosphorylation,
is not coupled to Gi and it activates PLC independent- TPβ undergoes internalization, unlike TPα (Walsh et
ly of PKA action (Miggin & Kinsella, 2002a; Chow et al., 2000). The internalization of TPβ is a dynamin
al., 2003). Through Gq and Gi, the murine IP receptor and arrestin-dependent process (Walsh et al., 2000).
activates PLC and inhibits the activity of AC, respective- Also palmitoylation of the C-tail of the receptor is im-
ly, which has been confirmed in studies using cicaprost portant, as it provides a proper spatial structure (Reid
(Lawler et al., 2001). PLC, by means of its product di- & Kinsella, 2007).
acylglycerol, then activates PKC. Nonetheless, it seems The cross-desensitization of the TP receptor by
that the mechanism underlying the activation of PKC PGI2 is another important process taking place when
depends on the type of cell (Chow et al., 2003). Due to both TxA2 and PGI2. In blood platelets TPα is the
these mechanisms, the ligand is capable of desensitizat- main isoform of TP (Habib et al., 1999). It is sus-
ing IP via PKC which phosphorylates the C-tail of the ceptible to desensitization by PGI2, which results in
receptor (Schermuly et al., 2007). As a result IP loses the suppression of the activity of TxA2 and makes blood
ability to activate AC. The intensity of the signal trans- platelets responsive only to PGI2. PGI2 and also
duction from the receptor can also be reduced in anoth- PGD2 cause desensitization of TPα through its phos-
er manner. Inhibition of AC isoforms 5 and 6 activity phorylation by PKA (Walsh et al., 2000; Walsh & Kin-
and their expression, which depends on PKA (Sobolews- sella, 2000; Foley et al., 2001; Wikström et al., 2008).
ki et al., 2004). This reduces capacity to increase the con- EP1 is yet another receptor with an influence on TP.
centration of cAMP in response to activation occurring EP1 activation causes the desensitization of TPα, and
through receptors associated with AC. Still, this process — to a lesser extent — also of TPβ, by PKC (Walsh
is transient and takes place after several hours of expo- & Kinsella, 2000). The same process, occurring along
sure to a ligand. After one day of exposure, the initial the same route, is observed after FP activation (Kel-
level and activity of AC isoforms 5 and 6 is restored ley-Hickie & Kinsella, 2004).
(Sobolewski et al., 2004). Transmission of the PGI2 signal can be reduced as
Activited receptors e.g., IP are once again resensi- a result of internalization of its the receptor IP under
tised to the ligand through endocytosis and recirculation. the influence of TP activation (Wilson et al., 2007a).
The described process is important in short-term regu- Reciprocally, activated IP reduces the amount of TPα
lation of receptors activity (Nilius et al., 2000). During in the cell membrane. This process is independent of
long-term exposure to a ligand, internalization and deg- PKA and most probably involves heterodimerization
radation of IP occurs, which does not depend on ist of IP with TPα and subsequent endocytosis of the di-
phosphorylation by PKC (Nilius et al., 2000; Smyth et mer (Wilson et al., 2007a).
al., 2000). These processes are more intense than de novo
Vol. 61
Cyclooxygenase pathways 647

AUTOREGULATION OF CYCLOOXYGENASE PATHWAYS Instead of inhibiting the synthesis of a single prostanoid,

AND THE FUTURE OF NON-STEROIDAL ANTI- it is possible to use another eicosanoid which has an op-
INFLAMMATORY DRUGS posite effect. The use of PGI2 analogues has shown thera-
peutic effects in patients suffering from thrombosis. In this
PGE2 plays a crucial role in neoplastic processes (Green- such an approach balances the effect of TxA2 without caus-
hough et al., 2009), therefore a preventive administration ing the negative consequences connected with its absence
of non-steroidal anti-inflammatory drugs (NSAID) reduces (Wilson et al., 2004).
the risk of multiple types of neoplasms (Ashok et al., 2011;
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