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Role of the Metabolic Stress Responses of Apoptosis and Autophagy in Tumor Suppression

  • E. White
Conference paper
Part of the Ernst Schering Foundation Symposium Proceedings book series (SCHERING FOUND, volume 2007/4)

Abstract

Metabolic stress is an important stimulus that promotes apoptosis-mediated tumor suppression. Metabolic stress arises in tumors from multiple factors that include insufficient nutrient supply caused by deficient angiogenesis and high metabolic demand of unrestrained cell proliferation. The high metabolic demand of tumor cells is only exacerbated by reliance on the inefficient process of glycolysis for energy production. Recently it has become clear that tumor cells survive metabolic stress through the catabolic process of autophagy. Autophagy also functions as a tumor suppression mechanism by preventing cell death and inflammation and by protecting the genome from damage and genetic instability. How autophagy protects the genome is not yet clear but may be related to its roles in sustaining metabolism or in the clearance of damaged proteins and organelles and the mitigation of oxidative stress. These findings illuminate the important role of metabolism in cancer progression and provide specific predictions for metabolic modulation in cancer therapy.

Keywords

Metabolic Stress Tumor Cell Death Tumor Cell Survival Genome Damage High Metabolic Demand 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Adams JM, Cory S (2007) Bcl-2-regulated apoptosis: mechanism and therapeutic potential. Curr Opin Immunol 19:488–496CrossRefPubMedGoogle Scholar
  2. Balkwill F, Charles KA, Mantovani A (2005) Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7:211–217CrossRefPubMedGoogle Scholar
  3. Boya P, Gonzalez-Polo RA, Casares N, Perfettini JL, Dessen P, Larochette N, Metivier D, Meley D, Souquere S, Yoshimori T et al (2005) Inhibition of macroautophagy triggers apoptosis. Mol Cell Biol 25:1025–1040CrossRefPubMedGoogle Scholar
  4. Condeelis J, Pollard JW (2006) Macrophages: obligate partners for tumor cell migration, invasion and metastasis. Cell 124:263–266CrossRefPubMedGoogle Scholar
  5. Cuconati A, White E (2002) Viral homologs of BCL-2: role of apoptosis in the regulation of virus infection. Genes Dev 16:2465–2478CrossRefPubMedGoogle Scholar
  6. Degenhardt K, Chen G, Lindsten T, White E (2002) BAX and BAK mediate p53-independent suppression of tumorigenesis. Cancer Cell 2:193–203CrossRefPubMedGoogle Scholar
  7. Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, Mukherjee C, Shi Y, Gelinas C, Fan Y et al (2006) Autophagy promotes tumor cell survival and restricts necrosis, inflammation and tumorigenesis. Cancer Cell 10:51–64CrossRefPubMedGoogle Scholar
  8. Fesik SW (2005) Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev 5:876–885CrossRefGoogle Scholar
  9. Folkman J (2006) Angiogenesis. Annu Rev Med 57:1–18CrossRefPubMedGoogle Scholar
  10. Gelinas C, White E (2005) BH3-only proteins in control: specificity regulates MCL-1 and BAK-mediated apoptosis. Genes Dev 19:1263–1268CrossRefPubMedGoogle Scholar
  11. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70CrossRefPubMedGoogle Scholar
  12. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K, Saito I, Okano H et al (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441:885–889CrossRefPubMedGoogle Scholar
  13. Jin S, White E (2007) Role of autophagy in cancer: management of metabolic stress. Autophagy 3:28–31PubMedGoogle Scholar
  14. Jin S, DiPaola RS, Mathew R, White E (2007) Metabolic catastrophe as a means to cancer cell death. J Cell Sci 120:379–383CrossRefPubMedGoogle Scholar
  15. Karantza-Wadsworth V, White E (2007) Role of autophagy in breast cancer. Autophagy 3:610–613PubMedGoogle Scholar
  16. Karantza-Wadsworth V, Patel S, Kravchuk O, Chen G, Mathew R, Jin S, White E (2007) Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev 21:1621–1635CrossRefPubMedGoogle Scholar
  17. Klionsky DJ (2007) Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 8:931–937CrossRefPubMedGoogle Scholar
  18. Komatsu M, Waguri S, Ueno T, Iwata J, Murata S, Tanida I, Ezaki J, Mizushima N, Ohsumi Y, Uchiyama Y et al (2005) Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol 169:425–434CrossRefPubMedGoogle Scholar
  19. Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E et al (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441:880–884CrossRefPubMedGoogle Scholar
  20. Komatsu M, Waguri S, Koike M, Sou YS, Ueno T, Hara T, Mizushima N, Iwata JI, Ezaki J, Murata S et al (2007) Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 131:1149–1163CrossRefPubMedGoogle Scholar
  21. Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, Ohsumi Y, Tokuhisa T, Mizushima N (2004) The role of autophagy during the early neonatal starvation period. Nature 432:1032–1036CrossRefPubMedGoogle Scholar
  22. Levine B, Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132:27–42CrossRefPubMedGoogle Scholar
  23. Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, Levine B (1999) Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402:672–676CrossRefPubMedGoogle Scholar
  24. Mathew R, White E (2007) Why sick cells produce tumors: the protective role of autophagy. Autophagy 3:502–505PubMedGoogle Scholar
  25. Mathew R, Karantza-Wadsworth V, White E (2007a) Role of autophagy in cancer. Nat Rev Cancer 7:961–967CrossRefPubMedGoogle Scholar
  26. Mathew R, Kongara S, Beaudoin B, Karp CM, Bray K, Degenhardt K, Chen G, Jin S, White E (2007b) Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev 21:1367–1381CrossRefPubMedGoogle Scholar
  27. Mizushima N (2007) Autophagy: process and function. Genes Dev 21:2861–2873CrossRefPubMedGoogle Scholar
  28. Nelson DA, Tan TT, Rabson AB, Anderson D, Degenhardt K, White E (2004) Hypoxia and defective apoptosis drive genomic instability and tumorigenesis. Genes Dev 18:2095–2107CrossRefPubMedGoogle Scholar
  29. Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, Rosen J, Eskelinen EL, Mizushima N, Ohsumi Y et al (2003) Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest 112:1809–1820PubMedGoogle Scholar
  30. Tan TT, Degenhardt K, Nelson DA, Beaudoin B, Nieves-Neira W, Bouillet P, Villunger A, Adams JM, White E (2005) Key roles of BIM-driven apoptosis in epithelial tumors and rational chemotherapy. Cancer Cell 7:227–238CrossRefPubMedGoogle Scholar
  31. Vousden KH, Lane DP (2007) p53 in health and disease. Nat Rev Mol Cell Biol 8:275–283CrossRefPubMedGoogle Scholar
  32. Warburg O (1956) On respiratory impairment in cancer cells. Science 124:269–270PubMedGoogle Scholar
  33. White E (2006) Mechanisms of apoptosis regulation by viral oncogenes in infection and tumorigenesis. Cell Death Differ 13:1371–1377CrossRefPubMedGoogle Scholar
  34. Wu H, Tschopp J, Lin SC (2007) Smac mimetics and TNFalpha: a dangerous liaison? Cell 131:655–658CrossRefPubMedGoogle Scholar
  35. Yue Z, Jin S, Yang C, Levine AJ, Heintz N (2003) Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci U S A 100:15077–15082CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2008

Authors and Affiliations

  1. 1.Department of Molecular Biology and BiochemistryRutgers University, Cancer Institute of New JerseyPiscatawayUSA

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