Autophagy: cell death or survival strategy?

O.V. Kovaleva, M.S. Shitova, I.B. Zborovskaya,

DOI:

https://doi.org/10.21320/2500-2139-2014-7-2-103-113

The interaction between proliferation, differentiation, and programmed cell death is an integral part of the life-sustaining activity of multicellular organisms. The imbalance between these processes underlies the development of many human diseases. Understanding molecular mechanisms of these processes is important for identifying new diagnostic and therapeutic targets. During the last decade, the autophagy processed and its role in the cell life and death became a subject of great scientific interest. Autophagy represents a mechanism of intracellular substance utilization. Autophagy is a process that occurs in all cells under normal conditions. But under certain circumstances, this process can result in the cell death. Impaired autophagy significantly contributes into the development of some diseases (cancer, neurodegenerative and cardiovascular disorders etc.).

  • O.V. Kovaleva N.N. Blokhin Russian Cancer Research Center, RAMS, Moscow, Russian Federation ; ФГБУ «Российский онкологический научный центр им. Н.Н. Блохина» РАМН, Москва, Российская Федерация
  • M.S. Shitova N.N. Blokhin Russian Cancer Research Center, RAMS, Moscow, Russian Federation ; ФГБУ «Российский онкологический научный центр им. Н.Н. Блохина» РАМН, Москва, Российская Федерация
  • I.B. Zborovskaya N.N. Blokhin Russian Cancer Research Center, RAMS, Moscow, Russian Federation ; ФГБУ «Российский онкологический научный центр им. Н.Н. Блохина» РАМН, Москва, Российская Федерация
  1. Galluzzi L., Vitale I., Abrams J.M. et al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ. 2012; 19(1): 107–20. DOI: https://doi.org/10.1038/cdd.2011.96
  2. Kerr J.F., Wyllie A.H., Currie A.R. Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 1972; 26: 239–57. DOI: https://doi.org/10.1038/bjc.1972.33
  3. Wong R.S. Apoptosis in cancer: from pathogenesis to treatment. J. Exp. Clin. Cancer Res. 2011; 26: 30–87. DOI: https://doi.org/10.1186/1756-9966-30-87
  4. Hu Y., Benedict M.A., Ding L., Nunez G. Role of cytochrome c and dATP/ ATP hydrolysis in Apaf-1-mediated caspase-9 activation and apoptosis. EMBO J. 1999; 18: 3586–95. DOI: https://doi.org/10.1093/emboj/18.13.3586
  5. Saelens X., Festjens N., Vande Walle L. et al. Toxic proteins released from mitochondria in cell death. Oncogene 2004; 23(16): 2861–74. DOI: https://doi.org/10.1038/sj.onc.1207523
  6. Altieri D.C. Surviving in apoptosis control and cell cycle regulation in cancer. Prog. Cell Cycle Res. 2003; 5: 447–52.
  7. Tamm I., Wang Y., Sausville E. et al. IAP-family protein surviving inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs. Cancer Res. 1998; 58(23): 5315–20.
  8. Padanilam B.J. Cell death induced by acute renal injury: a perspective on the contributions of apoptosis and necrosis. Am. J. Physiol. Renal. Physiol. 2003; 284(4): F608–27. DOI: https://doi.org/10.1152/ajprenal.00284.2002
  9. Hoste E., Kemperman P., Devos M. et al. Caspase-14 is required for filaggrin degradation to natural moisturizing factors in the skin. J. Invest. Dermatol. 2011; 131(11): 2233–41. DOI: https://doi.org/10.1038/jid.2011.153
  10. Levine B., Klionsky D.J. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev. Cell 2004; 6(4): 463–77. DOI: https://doi.org/10.1016/S1534-5807(04)00099-1
  11. Okada H., Mak T.W. Pathways of apoptotic and non-apoptotic death in tumor cells. Nat. Rev. Cancer 2004; 4(8): 592–603. DOI: https://doi.org/10.1038/nrc1412
  12. Kaminskyy V., Zhivotovsky B. Proteases in autophagy. Biochimica er Biophysica Acta. 2012; 1824: 44–50. DOI: https://doi.org/10.1016/j.bbapap.2011.05.013
  13. Mijaljica D., Prescott M., Devenish R.J. Microautophagy in mammalian cells: Revisiting a 40-year-old conundrum. Autophagy 2011; 7: 673–82. DOI: https://doi.org/10.4161/auto.7.7.14733
  14. Klionsky DJ., Codogno P., Cuervo A.M. et al. A comprehensive glossary of autophagy-related molecules and processes. Autophagy 2010; 6(4): 438–48. DOI: https://doi.org/10.4161/auto.6.4.12244
  15. Massey A.C., Zhang C., Cuervo A.M. Chaperone-mediated autophagy in aging and disease. Curr. Top. Dev. Biol. 2006; 73: 205–35. DOI: https://doi.org/10.1016/S0070-2153(05)73007-6
  16. Kimmelman A.C. The dynamic nature of autophagy in cancer. Genes Dev. 2011; 25(19): 1999–2010. DOI: https://doi.org/10.1101/gad.17558811
  17. Reggiori F., Tucker K.A., Stromhaug P.E., Klionsky D.J. The Atg1-Atg13 complex regulates Atg9 and Atg23 retrieval transport from the pre-autophagosomal structure. Dev. Cell 2004; 6(1): 79–90. DOI: https://doi.org/10.1016/S1534-5807(03)00402-7
  18. Wang C.W., Klionsky D.J. The molecular mechanism of autophagy. Mol. Med. 2003; 9: 65–76. DOI: https://doi.org/10.1007/BF03402040
  19. Teter S.A., Klionsky D.J. Transport of proteins to the yeast vacuole: autophagy, cytoplasm-to-vacuole targeting, and role of the vacuole in degradation. Semin. Cell Dev. Biol. 2000; 11(3): 173–9. DOI: https://doi.org/10.1006/scdb.2000.0163
  20. Chen N., Debnath J. Autophagy and Tumorigenesis. FEBS Lett. 2010; 584(7): 1427–35. DOI: https://doi.org/10.1016/j.febslet.2009.12.034
  21. Guertin D.A., Sabatini D.M. Defining the role of mTOR in cancer. Cancer Cell 2007; 12: 9–22. DOI: https://doi.org/10.1016/j.ccr.2007.05.008
  22. He C., Klionsky D.J. Regulation Mechanisms and Signaling Pathways of Autophagy. Annu. Rev. Genet. 2009; 43: 67–93. DOI: https://doi.org/10.1146/annurev-genet-102808-114910
  23. Zhou H., Huang S. The complexes of mammalian target of rapamycin. Curr. Protein Pept. Sci. 2010; 11: 409–24. DOI: https://doi.org/10.2174/138920310791824093
  24. Teter T., Hall M.N. TOR, a central controller of cell growth. Cell 2000; 103(2): 253–62. DOI: https://doi.org/10.1016/S0092-8674(00)00117-3
  25. Tee A.R., Manning B.D., Roux P.P., Cantley L.C., Blenis J. Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr. Biol. 2003; 13: 1259–68. DOI: https://doi.org/10.1016/S0960-9822(03)00506-2
  26. Shackelford D.B., Shaw R.J. The LKB1-AMPK pathway: metabolism and growth control in tumor suppression. Nat. Rev. Cancer 2009; 9: 563–75. DOI: https://doi.org/10.1038/nrc2676
  27. Liang J., Shao SH., Xu Z.X. et al. The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis. Nat. Cell Biol. 2007; 9: 218–24. DOI: https://doi.org/10.1038/ncb1537
  28. Feng Z., Hu W., Stanchina E. et al. The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways. Cancer Res. 2007; 67: 3043–53. DOI: https://doi.org/10.1158/0008-5472.CAN-06-4149
  29. Mortensen M., Watson A.S., Simon A.K. Lack of autophagy in the hematopoietic system leads to loss of hematopoietic stem cell function and dysregulated myeloid proliferation. Autophagy 2011; 7(9): 1069–70. DOI: https://doi.org/10.4161/auto.7.9.15886
  30. Mortensen M., Soilleux E.J., Djordjevic G. et al. The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance. J. Exp. Med. 2011; 208: 455–67. DOI: https://doi.org/10.1084/jem.20101145
  31. Pua H.H., Komatsu M., He Y.W. Autophagy is essential for mitochondrial clearance in mature T lymphocytes. J. Immunol. 2009; 182: 4046–55. DOI: https://doi.org/10.4049/jimmunol.0801143
  32. Pua H.H., Dzhagalov I., Chuck M. et al. A critical role for the autophagy gene Atg5 in T cell survival and proliferation. J. Exp. Med. 2007; 204: 25–31. DOI: https://doi.org/10.1084/jem.20061303
  33. Pua H.H., He Y.W. Maintaining T lymphocyte homeostasis: another duty of autophagy. Autophagy 2007; 3: 266–7. DOI: https://doi.org/10.4161/auto.3908
  34. Miller B.C., Zhao Z., Stephenson L.M. et al. The autophagy gene Atg5 plays an essential role in B lymphocyte development. Autophagy 2008; 4: 309–14. DOI: https://doi.org/10.4161/auto.5474
  35. Novak I., Kirkin V., McEwan D.G. et al. Nix is a selective autophagy receptor for mitochondrial clearance. EMBO Rep. 2010; 11(1): 45–51. DOI: https://doi.org/10.1038/embor.2009.256
  36. Kundu M., Lindsten T., Yang C.Y. et al. Ulk1 plays a critical role in the autophagic clearance of mitochondria and ribosomes during reticulocyte maturation. Blood 2008; 112: 1493–502. DOI: https://doi.org/10.1182/blood-2008-02-137398
  37. Raslova H., Kauffmann A., Sekkai D. et al. Interrelation between polyploidization and megakaryocyte differentiation: a gene profiling approach. Blood. 2007; 109: 3225–34. DOI: https://doi.org/10.1182/blood-2006-07-037838
  38. Delgado M.A., Elmaoued R.A., Davis A.S., Kyei G., Deretic V. Toll-like receptors control autophagy. EMBO J. 2008; 27: 1110–21. DOI: https://doi.org/10.1038/emboj.2008.31
  39. Shi C.S., Kehrl J.H. MyD88 and Trif target Beclin 1 to trigger autophagy in macrophages. J. Biol. Chem. 2008; 283: 33175–82. DOI: https://doi.org/10.1074/jbc.M804478200
  40. Xu Y., Jagannath C., Liu X.D. et al. Toll-like receptor 4 is a sensor for autophagy associated with innate immunity. Immunity. 2007; 27: 135–44. DOI: https://doi.org/10.1016/j.immuni.2007.05.022
  41. Канцерогенез. Под ред. Д.Г. Заридзе. М.: Медицина, 2004. [Kantserogenez. Pod red. D.G. Zaridze (Carcinogenesis. Ed. by: D.G. Zaridze). M.: Meditsina, 2004.]
  42. Liang X.H., Jackson S., Seaman M. et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999; 402: 672–6. DOI: https://doi.org/10.1038/45257
  43. Yue Z., Jin S., Yang C., Levine A.J., Heintz N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc. Natl. Acad. Sci. U S A 2003; 100: 15077–82. DOI: https://doi.org/10.1073/pnas.2436255100
  44. Qu X., Yu J., Bhagat G. et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J. Clin. Invest. 2003; 112: 1809–20. DOI: https://doi.org/10.1172/JCI20039
  45. Karantza-Wadsworth V., Patel S., Kravchuk O. et al. Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev. 2007; 21: 1621–35. DOI: https://doi.org/10.1101/gad.1565707
  46. Meek D.W. Tumor suppression by p53: a role for the DNA damage response? Nat. Rev. Cancer 2009; 9: 714–23. DOI: https://doi.org/10.1038/nrc2716
  47. Degenhardt K., Mathew R., Beaudoin B. et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 2006; 10: 51–64. DOI: https://doi.org/10.1016/j.ccr.2006.06.001
  48. DeNardo D., Johansson M., Coussens L. Immune cells as mediators of solid tumor metastasis. Cancer Metast. Rev. 2008; 27: 11–8. DOI: https://doi.org/10.1007/s10555-007-9100-0
  49. DeNardo D.G., Barreto J.B., Andreu P. et al. CD4+ T Cells Regulate Pulmonary Metastasis of Mammary Carcinomas by Enhancing Protumor Properties of Macrophages. Cancer Cell 2009; 16: 91–102. DOI: https://doi.org/10.1016/j.ccr.2009.06.018
  50. Bingle L., Brown N.J., Lewis C.E. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J. Pathol. 2002; 196: 254–65. DOI: https://doi.org/10.1002/path.1027
  51. Young A.R., Narita M., Ferreira M. et al. Autophagy mediates the mitotic senescence transition. Genes Dev. 2009; 23: 798–803. DOI: https://doi.org/10.1101/gad.519709
  52. Petiot A., Ogier-Denis E., Blommaart E.F., Meijer AJ., Codogno P. Distinct classes of phosphatidylinositol 3¢-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells. J. Biol. Chem. 2000; 275: 992–8. DOI: https://doi.org/10.1074/jbc.275.2.992
  53. Luiken J.J., Aerts J.M., Meijer A.J. The role of the intralysosomal pH in the control of autophagic proteolytic flux in rat hepatocytes. Eur. J. Biochem. 1996; 235: 564–73. DOI: https://doi.org/10.1111/j.1432-1033.1996.00564.x-i2
  54. Yamamoto A., Tagawa Y., Yoshimori T. et al. Bafilomycin A1 prevents maturation of autophagic vacuoles by inhibiting fusion between autophagosomes and lysosomes in rat hepatoma cell line, H-4-II-E cells. Cell Struct. Funct. 1998; 23: 33–42. DOI: https://doi.org/10.1247/csf.23.33
  55. Ito H., Daido S., Kanzawa T., Kondo S., Kondo Y. Radiation-induced autophagy is associated with LC3 and its inhibition sensitizes malignant glioma cells. Int. J. Oncol. 2005; 26: 1401–10. DOI: https://doi.org/10.3892/ijo.26.5.1401
  56. Lomonaco S.L., Finniss S., Xiang C. et al. The induction of autophagy by gamma-radiation contributes to the radioresistance of glioma stem cells. Int. J. Cancer 2009; 125: 717–22. DOI: https://doi.org/10.1002/ijc.24402
  57. Shingu T., Fujiwara K., Bogler O. et al. Stage-specific effect of inhibition of autophagy on chemotherapy-induced cytotoxicity. Autophagy 2009; 5: 537–9. DOI: https://doi.org/10.4161/auto.5.4.8164
  58. Vazquez-Martin A., Oliveras-Ferraros C., Menendez J.A. Autophagy facilitates the development of breast cancer resistance to the anti-HER2 monoclonal antibody trastuzumab. PLoS One 2009; 4: e6251. DOI: https://doi.org/10.1371/journal.pone.0006251
  59. Abedin M.J., Wang D., McDonnell M.A., Lehmann U., Kelekar A. Autophagy delays apoptotic death in breast cancer cells following DNA damage. Cell Death Differ. 2007; 14: 500–10. DOI: https://doi.org/10.1038/sj.cdd.4402039
  60. Kim R.H., Coates J.M., Bowles T.L. et al. Arginine deiminase as a novel therapy for prostate cancer induces autophagy and caspase-independent apoptosis. Cancer Res. 2009; 69: 700–8. DOI: https://doi.org/10.1158/0008-5472.CAN-08-3157
  61. Bellodi C., Lidonnici M.R., Hamilton A. et al. Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosomepositive cells, including primary CML stem cells. J. Clin. Invest. 2009; 119: 1109–23. DOI: https://doi.org/10.1172/JCI35660
  62. Carew J.S., Nawrocki S.T., Kahue C.N. et al. Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-Abl-mediated drug resistance. Blood 2007; 10: 313–22. DOI: https://doi.org/10.1182/blood-2006-10-050260
  63. Ertmer A., Huber V., Gilch S. et al. The anticancer drug imatinib induces cellular autophagy. Leukemia 2007; 21: 936–42. DOI: https://doi.org/10.1038/sj.leu.2404606
  64. Kamitsuji Y., Kuroda J., Kimura S. et al. The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias. Cell Death Differ. 2008; 15: 1712–22. DOI: https://doi.org/10.1038/cdd.2008.107
  65. Goussetis D.J., Altman J.K., Glaser H. et al. Autophagy is a critical mechanism for the induction of the antileukemic effects of arsenic trioxide. J. Biol. Chem. 2010; 285: 29989–97. DOI: https://doi.org/10.1074/jbc.M109.090530
  66. Qian W., Liu J., Jin J. et al. Arsenic trioxide induces not only apoptosis but also autophagic cell death in leukemia cell lines via up-regulation of Beclin-1. Leuk. Res. 2007; 31: 329–39. DOI: https://doi.org/10.1016/j.leukres.2006.06.021
  67. Charoensuk V., Gati WP., Weinfeld M. et al. Differential cytotoxic effects of arsenic compounds in human acute promyelocytic leukemia cells. Toxicol. Appl. Pharmacol. 2009; 239: 64–70. DOI: https://doi.org/10.1016/j.taap.2009.05.016
  68. Chiarini F., Grimaldi C., Ricci F. et al. Activity of the novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVPBEZ235 against T-cell acute lymphoblastic leukemia. Cancer Res. 2010; 70: 8097–107. DOI: https://doi.org/10.1158/0008-5472.CAN-10-1814
  69. Crazzolara R., Bradstock K.F., Bendall L.J. RAD001 (everolimus) induces autophagy in acute lymphoblastic leukemia. Autophagy 2009; 5: 727–8. DOI: https://doi.org/10.4161/auto.5.5.8507
  70. Crazzolara R., Cisterne A., Thien M. et al. Potentiating effects of RAD001 (everolimus) on vincristine therapy in childhood acute lymphoblastic leukemia. Blood 2009; 113: 3297–306. DOI: https://doi.org/10.1182/blood-2008-02-137752
  71. Puissant A., Auberger P. AMPK- and p62/SQSTM1-dependent autophagy mediate resveratrol-induced cell death in chronic myelogenous leukemia. Autophagy 2010; 6(5): 655–7. DOI: https://doi.org/10.4161/auto.6.5.12126
  72. Puissant A., Robert G., Fenouille N. et al. Resveratrol promotes autophagic cell death in chronic myelogenous leukemia cells via JNK mediated p62/SQSTM1 expression and AMPK activation. Cancer Res. 2010; 70: 1042–52. DOI: https://doi.org/10.1158/0008-5472.CAN-09-3537
  73. Kroemer G., Levine B. Autophagic cell death: the story of a misnomer. Nat. Rev. Mol. Cell Biol. 2008; 9: 1004–10. DOI: https://doi.org/10.1038/nrm2529
  74. Turcotte S., Chan D.A., Sutphin P.D. et al. A molecule targeting VHLdeficient renal cell carcinoma that induces autophagy. Cancer Cell. 2008; 14: 90–102. DOI: https://doi.org/10.1016/j.ccr.2008.06.004
  75. Kanzawa T., Germano I.M., Komata T. et al. Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells. Cell Death Differ. 2004; 11: 448–57. DOI: https://doi.org/10.1038/sj.cdd.4401359

Keywords:

apoptosis, autophagy, carcinogenesis

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01.07.2025

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Vol. 7 No. 2 (2014)
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Kovaleva O.V., Shitova M.S., Zborovskaya I.B. Autophagy: cell death or survival strategy?. Clinical Oncohematology. Basic Research and Clinical Practice. 2025;7(2):103–113. doi:10.21320/2500-2139-2014-7-2-103-113.