NIH Public Access

Author Manuscript
Autophagy. Author manuscript; available in PMC 2009 October 30.
Published in final edited form as:
NIH-PA Author Manuscript

Autophagy. 2007 ; 3(1): 28–31.

Role of Autophagy in Cancer:

Management of Metabolic Stress

Shengkan Jin1,3 and Eileen White2,3

1 Department of Pharmacology; University of Medicine and Dentistry of New Jersey; Robert Wood

Johnson Medical School

2Center for Advanced Biotechnology and Medicine; Department of Molecular Biology and
Biochemistry; Rutgers University
3 Cancer Institute of New Jersey

Abstract
NIH-PA Author Manuscript

Human breast, ovarian, and prostate tumors display allelic loss of the essential autophagy gene
beclin1 with high frequency, and an increase in the incidence of tumor formation is observed in
beclin1+/− mutant mice. These findings suggest a role for beclin1 and autophagy in tumor
suppression; however, the mechanism by which this occurs has been unclear. Autophagy is a bulk
degradation process whereby organelles and cytoplasm are engulfed and targeted to lysosomes for
proteolysis,1,2 There is evidence that autophagy sustains cell survival during nutrient deprivation
through catabolism, but also that autophagy is a means of achieving cell death when executed to
completion. If or how either of these diametrically opposing functions proposed for autophagy may
be related to tumor suppression is unknown. We found that metabolic stress is a potent trigger of
apoptotic cell death, defects in which enable long-term survival that is dependent on autophagy both
in vitro and in tumors in vivo.3 These findings raise the conundrum whereby inactivation of a survival
pathway (autophagy) promotes tumorigenesis. Interestingly, when cells with defects in apoptosis are
denied autophagy, this creates the inability to tolerate metabolic stress, reduces cellular fitness, and
activates a necrotic pathway to cell death. This necrosis in tumors is associated with inflammation
and enhancement of tumor growth, due to the survival of a small population of surviving, but injured,
cells in a microenvironment that favors oncogenesis. Thus, by sustaining metabolism through
autophagy during periods of metabolic stress, cells can limit energy depletion, cellular damage, and
cell death by necrosis, which may explain how autophagy can prevent cancer, and how loss of a
NIH-PA Author Manuscript

survival function can be tumorigenic.

Keywords
autophagy; apoptosis; necrosis; Beclin1; cancer

Correspondence to: Shengkan Jin; Department of Pharmacology; 675 Hoes Lane; Piscataway, New Jersey 08854 USA; Tel.:
732.235.4329; Fax: 732.235.4073; Email: jinsh@umdnj.edu/Eileen White; CABM; 679 Hoes Lane; Piscataway, New Jersery 08854
USA; Tel.: 732.235.5329; Fax: 732.235.5795; Email: ewhite@cabm.rutgers.edu.
Addendum to: Autophagy Promotes Tumor Cell Survival and Restricts Necrosis, Inflammation and Tumorigenesis
K. Degenhardt, R. Mathew, B. Beaudoin, K. Bray, D. Anderson, G. Chen, C. Mukherjee, Y. Shi, C. Gelinas, Y. Fan, D.A. Nelson, S. Jin
and E. White
Previously published online a an Autophagy E-publication:
http://www.landesbioscience.com/journals/autophagy/abstract.php?id=3269
 Jin and White Page 2

APOPTOSIS IS A CELLULAR QUALITY CONTROL MECHANISM

Cancer results from the accumulation of mutations that deregulate cell growth, checkpoints,
NIH-PA Author Manuscript

cell death, and conditions in the tumor microenvironment in a manner that favors tumor growth
and progression.4 Cell death by apoptosis is an important means to purge abnormal, emerging
cancer cells, and thus is a prominent mechanism for tumor suppression.5,6 Apoptosis is also a
common cellular response to stress and many of the molecular events that promote
tumorigenesis create or amplify cellular stress. For these and other reasons, defects in apoptosis
commonly evolve during tumorigenesis, which further promotes tumor growth and treatment
resistance. Once apoptosis is inactivated, tumor cells clearly possess a survival advantage;
however, it may be the survival of the damaged “undead” cells that promotes tumor progression
through the manifestation and preservation of genome damage and chromosome instability.7,
8

METABOLIC STRESS IN TUMORS INDUCES APOPTOSIS THAT WHEN

INACTIVATED REVEALS AUTOPHAGY
Metabolic stress is a common feature of solid tumors caused by inadequate vascularization that
results in nutrient, growth factor, and oxygen deprivation.9 Once tumors exceed a diameter of
1–2 mm, angiogenesis must occur to ameliorate metabolic stress associated with the central
and most metabolically deprived hypoxic tumor domain. Metabolic stress also occurs in mature
NIH-PA Author Manuscript

tumors, where interruption in the blood supply is common due to vascular collapse because
vascularization is abnormal. Solid tumors with defects in apoptosis survive this metabolic
stress, and autophagy localizes to these hypoxic tumor regions.3 Growth factor-dependent
hematopoietic cells also undergo autophagy upon growth factor deprivation, suggesting that
the trigger for metabolic stress can be cell type-dependent.10

AUTOPHAGY IS A SURVIVAL PATHWAY UTILIZED BY TUMOR CELLS TO

SURVIVE METABOLIC STRESS
Compromising autophagy in apoptosis-defective tumor cells substantially impairs survival in
metabolic stress conditions in vitro and in tumors in vivo, establishing that autophagy is a
survival pathway utilized to sustain viability during periods of nutrient limitation.3 Indeed,
autophagy functions to sustain metabolism during periods of growth factor deprivation of
hematopoietic cells10 and upon nutrient deprivation in normal mouse development.11 This
suggests that autophagy is playing the same role of sustaining cellular metabolism and nutrient
homeostasis in both normal and tumor cells, and in divergent cell types. Paradoxically, defects
in autophagy are associated with increased tumorigenesis: human breast, ovarian and prostate
tumors have allelic loss of the essential autophagy gene beclin1 with high frequency and
NIH-PA Author Manuscript

beclin1 heterozygous mutant mice are tumor-prone.12–14 Moreover, beclin1+/− immortal

epithelial cells that display enhanced susceptibility to metabolic stress are also more
tumorigenic than their beclin1+/+ counterparts, and this tumorigenicity is greatly amplified by
an apoptosis defect.3 Thus, the impaired stress response and increased tumorigenicity that result
from a deficiency in autophagy are likely linked, and synergize with defective apoptosis to
promote tumor growth. How then does compromising tumor cell survival through deficient
autophagy promote tumor growth?

AUTOPHAGY AS A PROTEIN AND ORGANELLE QUALITY CONTROL

MECHANISM
Elegant studies with mutant mice with targeted inactivation of essential autophagy genes have
demonstrated that defects in autophagy result in the accumulation of ubiquitinated, and likely

Autophagy. Author manuscript; available in PMC 2009 October 30.

 Jin and White Page 3

damaged, proteins that promote cellular degeneration.15–17 Similarly, there is evidence to

support a role for autophagy in the elimination of damaged or malfunctioning organelles,
particularly mitochondria.18,19 Proper mitochondrial quality control may be critical for
NIH-PA Author Manuscript

preventing oxidative damage through the generation of reactive oxygen species, a toxic
byproduct of mitochondrial malfunction. Although much remains to be resolved, this suggests
that autophagy is required not only as an alternate means to generate ATP during periods of
starvation, but that it also has a role in maintaining homeostasis through protein and organelle
quality control. These functions of autophagy may be particularly critical in situations of
metabolic stress where ATP is limiting and cellular damage accumulates at an accelerated rate.
The role of autophagy may be particularly critical for tumors, which are regularly subjected to
stress that is exacerbated by a metabolic state dependent on the inefficient process of aerobic
glycolysis.20 Furthermore, as tumors frequently disable the ultimate means for the clean
elimination of damaged cells, the cellular quality control mechanism of apoptosis, this ensures
the preservation of damaged cells that may contribute to tumor progression.

RESOLVING THE PARADOX: HOW DEFECTS IN A SURVIVAL PATHWAY CAN

PROMOTE TUMORIGENESIS
We propose that it is the survival of a small number of “undead”, injured cells in a damaging
microenvironment, rather than the large-scale survival of healthy cells in hospitable conditions,
that leads to tumorigenesis. If so, how does this happen?
NIH-PA Author Manuscript

Role of autophagy in cancer: The metabolic stress management hypothesis

Recycling of cellular garbage: Maintenance of homeostasis—It is becoming clear
that autophagy facilitates the adaptation to metabolic stress in both normal and cancer cells.
This inability to adapt to metabolic stress results in insufficient ATP generation, which can
broadly have an impact upon cellular functions leading either directly or indirectly to genome
damage. By recycling cellular proteins and organelles, autophagy may serve the vital function
of maintaining ATP levels during periods of nutrient limitation as a means to ensure the fidelity
of vital cellular processes such as DNA replication, transcription, protein synthesis and mitosis.
In tumor cells where both the cellular (apoptosis) and intracellular (autophagy) quality control
mechanisms are commonly disabled, this creates the means to accelerate the generation of
damaged cells through failure to maintain energy homeostasis (Fig. 1). Accelerated generation
of damaged organelles, particularly mitochondria, may exacerbate this process. Apoptotic
defects in tumor cells cause manifestation of chromosome instability in response to metabolic
stress,7,8,21 and it will be of great interest to determine if this process is compounded by
deficient autophagy.
NIH-PA Author Manuscript

Limit the generation of cellular garbage: Protein and organelle quality control
—Under stress conditions, damaged proteins and organelles may accumulate at an accelerated
rate, requiring activation of a deliberate mechanism such as autophagy to facilitate their
elimination. This failure of protein/organelle quality control to curtail the accumulation of
damaged proteins and organelles through autophagy may again have a broad impact on cellular
functions leading either directly or indirectly to genome damage that promotes tumorigenesis
(Fig. 1). As in neurons from mice with autophagy deficiencies, the aberrant accumulation of
ubiquitinated proteins is also observed in human tumors,22 but whether defective autophagy
is responsible is not known. It will be worthwhile to determine how cellular damage resulting
from enhanced susceptibility to metabolic stress caused by deficient autophagy is manifested.

Take the cellular garbage away: Limiting necrosis and inflammation—The failure
of energy homeostasis and cellular and intracellular quality control confers otherwise death-
refractory cells with inherent susceptibility to metabolic stress.3 Unable to undergo apoptosis,

Autophagy. Author manuscript; available in PMC 2009 October 30.

 Jin and White Page 4

metabolic stress forces these autophagy- and apoptosis-defective cells into necrotic cell death
(Fig. 1).3 These findings revealed the means to activate an alternate death pathway (necrosis)
in otherwise death (apoptosis)-refractory tumor cells, a paradigm that should be exploited
NIH-PA Author Manuscript

therapeutically. However, diverting cells from apoptotic to necrotic cell death profoundly alters
the tumor microenvironment, producing inflammatory cell infiltration and cytokine signaling,
the consequences of which require further investigation.3 Necrosis is a common feature of
human tumors and associated with poor prognosis. By provoking an inflammatory response,
necrosis, by analogy with wound healing, may facilitate proliferation and angiogenesis
favoring tumor growth.23–25 As defects in both autophagy and apoptosis provide the genetic
means to specifically induce necrosis in response to metabolic stress, the contribution of
components of the inflammatory response to tumor initiation and progression can be directly
tested. Examining the impact of a necrotic rather than apoptotic cell fate on proliferation,
angiogenesis, mutagenesis, genetic instability, the cytokine milieu, and the cellular immune
response may provide some of the answers.

MODULATION OF AUTOPHAGY FOR CANCER THERAPY: THE DOUBLE-

EDGED SWORD
The determination that autophagy functions to promote tumor cell survival reveals a plethora
of novel targets within that pathway for anti-cancer drug discovery. This ability to kill the
“unkillable” apoptosis-resistant tumor cells by combining inhibition of autophagy with
NIH-PA Author Manuscript

metabolic stress should be therapeutically exploited. Therapeutic induction of metabolic stress

in tumors, particularly with the advent of anti-angiogenic therapy, is now possible.9 Whether
this activates the autophagy survival pathway in tumors should be determined. The trade-off
here is that compromising autophagy is damaging to cells, some elements of which may
promote tumorigenesis not unlike many current anti-cancer cytotoxic therapeutics. Similarly,
understanding and defining the consequences of provoking an inflammatory response by
switching tumor cells from apoptosis to necrosis, and harnessing that response to facilitate
tumor eradication, needs further exploration.

Acknowledgments
We thank Thomasina Sharkey for assistance with preparation of the manuscript. We thank members of the White and
Jin laboratories for thoughtful comments and discussion.

References
1. Levine B, Klionsky DJ. Development by self-digestion; molecular mechanisms and biological
functions of autophagy. Dev Cell 2004;6:463–77. [PubMed: 15068787]
NIH-PA Author Manuscript

2. Mizushima N. The pleiotropic role of autophagy: From protein metabolism to bactericide. Cell Death
Differ 2005;12:1535–41. [PubMed: 16247501]
3. Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, Mukherjee C, Shi C, Gelinas
C, Fan Y, Nelson Da, Jin S, White E. Autophagy promotes tumor cell survival and restricts necrosis,
inflammation, and tumorigenesis. Cancer Cell 2006:51–64. [PubMed: 16843265]
4. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57–70. [PubMed: 10647931]
5. Cory S, Huang DC, Adams JM. The Bcl-2 family: Roles in cell survival and oncogenesis. Oncogene
2003;22:8590–607. [PubMed: 14634621]
6. Danial NN, Korsmeyer SJ. Cell death: Critical control points. Cell 2004;116:205–19. [PubMed:
14744432]
7. Degenhardt K, Chen G, Lindsten T, White E. Bax and Bak mediate p53-independent suppression of
tumorigenesis. Cancer Cell 2002;2:193–203. [PubMed: 12242152]
8. Nelson D, Tan TT, Rabson AB, Anderson D, Degenhardt K, White E. Hypoxia and defective apoptosis
drive genomic instability and tumorigenesis. Genes Dev 2004;18:2095–107. [PubMed: 15314031]

Autophagy. Author manuscript; available in PMC 2009 October 30.

 Jin and White Page 5

9. Folkman J. Angiogenesis and apoptosis. Seminars in Cancer Biology 2003;13:159–67. [PubMed:

12654259]
10. Lum JJ, Bauer DE, Kong M, Harris MH, Li C, Lindsten T, Thompson CB. Growth factor regulation
NIH-PA Author Manuscript

of autophagy and cell survival in the absence of apoptosis. Cell 2004;120:237–48. [PubMed:
15680329]
11. Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, Ohsumi Y, Tokuhisa T,
Mizushima N. The role of autophagy during the early neonatal starvation period. Nature
2004;432:1032–6. [PubMed: 15525940]
12. Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, Rosen J, Eskelinen EL, Mizushima N,
Ohsumi Y, Cattoretti G, Levine B. Promotion of tumorigenesis by heterozygous disruption of the
beclin 1 autophagy gene. J Clin Invest 2003;112:1809–20. [PubMed: 14638851]
13. Yue Z, Jin S, Yang C, Levine AJ, Heintz N. Beclin 1, an autophagy gene essential for early embryonic
development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci USA 2003;100:15077–82.
[PubMed: 14657337]
14. Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, Levine B. Induction of
autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999;402:672–6. [PubMed: 10604474]
15. Komatsu M, Waguri S, Ueno T, Iwata J, Murato S, Tanida I, Ezaki J, Mizushima N, Ohsumi Y,
Uchiyama Y, Kominami E, Tanaka K, Chiba T. Impairment of starvation-induced and constitutive
autophagy in Atg7-deficient mice. J Cell Biol 2005;169:425–34. [PubMed: 15866887]
16. Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M, Uchiyama Y,
Kominami E, Tanaka K. Loss of autophagy in the central nervous system causes neurodegeneration
NIH-PA Author Manuscript

in mice. Nature 2006:880–4. [PubMed: 16625205]

17. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M,
Mishima K, Saito I, Okano H, Mizushima N. Suppression of basal autophagy in neural cells causes
neurodegenerative disease in mice. Nature 2006;441:885–9. [PubMed: 16625204]
18. Jin S. Autophagy, mitochondrial quality control and oncogenesis. Autophagy 2006;2:80–4. [PubMed:
16874075]
19. Zhang Y, Qi H, Taylor R, Xu W, Liu LF, Jin S. Autophagy is required for mitochondria degradation
and optimal mitochondrial function in S. cerevisiae. 2006Submitted
20. Warburg O. On respiratory impairment in cancer cells. Science 1956;124:269–70. [PubMed:
13351639]
21. Tan TT, Degenhardt K, Nelson DA, Beaudoin B, Nieves-Neira W, Bouillet P, Villunger A, Adams
JM, White E. Key roles of BIM-driven apoptosis in epithelial tumors and rational chemotherapy.
Cancer Cell 2005;7:227–38. [PubMed: 15766661]
22. Iwaya K, Mukai K. Accumulation of ubiqutin-conjugated cytokeratin fragments in tumor cells. Semin
Cancer Biol 2005;15:309–18. [PubMed: 15907383]
23. Balkwill F, Charles KA, Mantovani A. Smoldering and polarized inflammation in the initiation and
promotion of malignant disease. Cancer Cell 2005;7:211–7. [PubMed: 15766659]
24. Balkwill F, Coussens LM. Cancer: An inflammatory link. Nature 2004;431:405–6. [PubMed:
NIH-PA Author Manuscript

15385993]
25. Zeh HJI, Lotze MT. Addicted to death. J Immunother 2005;28:1–9. [PubMed: 15614039]

Autophagy. Author manuscript; available in PMC 2009 October 30.

 Jin and White Page 6
NIH-PA Author Manuscript
NIH-PA Author Manuscript

Figure 1.
Role of apoptosis and autophagy in the response to metabolic stress in tumorigenesis. Excessive
metabolic stress induces organelle, protein, and DNA damage that potently stimulate apoptosis.
Apoptosis serves to eliminate potential damaged cells without induction of an inflammatory
response. This apoptotic response severely limits tumorigenesis of immortal epithelial cells,
with approximately one in a million cells eventually acquiring a stable genetic or epigenetic
change after two to three months of selection in vivo that permits tumor growth.7,8 Defects in
NIH-PA Author Manuscript

apoptosis, however, permit cells to survive metabolic stress in vitro, but also in vivo where
autophagy localizes to hypoxic tumor regions.3,7,8,21 Defects in apoptosis allow survival by
autophagy, however, the protection from metabolic stress conferred by autophagy may be
incomplete with the persistence of some tumor cells manifesting chromosome instability.8
Whereas defective apoptosis is sufficient to render immortal epithelial cells tumorigenic, the
manifestation of chromosome instability is associated with, and may expedite, tumor evolution.
7,8 Defects in autophagy caused by haploinsufficiency in beclin1 sensitize cells to metabolic
stress most likely by amplifying cellular damage. The ability of autophagy to limit apoptosis
is modest, if apparent at all, in the context of an intact apoptotic response. Although a slight
increase in tumor incidence is observed in immortal epithelial cells with allelic loss of
beclin1 and compromised autophagy, tumor growth is still due to clonal emergence.3
Tumorigenesis in this case may result from an increased mutation rate and escape from
apoptosis arising from the manifestation of cellular damage. In contrast, defects in apoptosis

Autophagy. Author manuscript; available in PMC 2009 October 30.

 Jin and White Page 7

and autophagy synergize to promote tumor growth.3 Impaired autophagy likely amplifies
cellular damage, compromising viability by activating necrotic cell death. Induction of necrosis
is less efficient than apoptosis and more potential tumor cells with unstable genomes survive
NIH-PA Author Manuscript

that have the potential to multiply. Finally, necrosis stimulates inflammation that has the
potential to substantially influence tumor growth by promoting angiogenesis and cell
proliferation.
NIH-PA Author Manuscript
NIH-PA Author Manuscript

Autophagy. Author manuscript; available in PMC 2009 October 30.