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Dual role of autophagy in hallmarks of cancer

Abstract

Evolutionarily conserved across eukaryotic cells, macroautophagy (herein autophagy) is an intracellular catabolic degradative process targeting damaged and superfluous cellular proteins, organelles, and other cytoplasmic components. Mechanistically, it involves formation of double-membrane vesicles called autophagosomes that capture cytosolic cargo and deliver it to lysosomes, wherein the breakdown products are eventually recycled back to the cytoplasm. Dysregulation of autophagy often results in various disease manifestations, including neurodegeneration, microbial infections, and cancer. In the case of cancer, extensive attention has been devoted to understanding the paradoxical roles of autophagy in tumor suppression and tumor promotion. In this review, while we summarize how this self-eating process is implicated at various stages of tumorigenesis, most importantly, we address the link between autophagy and hallmarks of cancer. This would eventually provide a better understanding of tumor dependence on autophagy. We also discuss how therapeutics targeting autophagy can counter various transformations involved in tumorigenesis. Finally, this review will provide a novel insight into the mutational landscapes of autophagy-related genes in several human cancers, using genetic information collected from an array of cancers.

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References

  1. Mizushima N. Autophagy: process and function. Genes Dev. 2007;21:2861–73.

    Article  CAS  PubMed  Google Scholar 

  2. Mizushima N, Yoshimori T, Levine B. Methods in mammalian autophagy research. Cell. 2010;140:313–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Aita VM, Liang XH, Murty VV, Pincus DL, Yu W, Cayanis E, et al. Cloning and genomic organization of beclin 1, a candidate tumor suppressor gene on chromosome 17q21. Genomics. 1999;59:59–65.

    Article  CAS  PubMed  Google Scholar 

  4. Ameisen JC. On the origin, evolution, and nature of programmed cell death: a timeline of four billion years. Cell Death Differ. 2002;9:367–93.

    Article  CAS  PubMed  Google Scholar 

  5. Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanisms. J Pathol. 2010;221:3–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Nixon RA. The role of autophagy in neurodegenerative disease. Nat Med. 2013;19:983–97.

    Article  CAS  PubMed  Google Scholar 

  7. Son JH, Shim JH, Kim K-H, Ha J-Y, Han JY. Neuronal autophagy and neurodegenerative diseases. Exp Mol Med. 2012;44:89–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Rabinowitz JD, White E. Autophagy and metabolism. Science. 2010;330:1344–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Karantza-Wadsworth V, Patel S, Kravchuk O, Chen G, Mathew R, Jin S, et al. Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev. 2007;21:1621–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bellot G, Garcia-Medina R, Gounon P, Chiche J, Roux D, Pouysségur J, et al. Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol Cell Biol. 2009;29:2570–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bauckman KA, Owusu-Boaitey N, Mysorekar IU. Selective autophagy: xenophagy. Methods. 2015;75:120–7.

    Article  CAS  PubMed  Google Scholar 

  12. Chandra P, Kumar D. Selective autophagy gets more selective: uncoupling of autophagy flux and xenophagy flux in Mycobacterium tuberculosis-infected macrophages. Autophagy. 2016;12:608–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Levine B. Eating oneself and uninvited guests: autophagy-related pathways in cellular defense. Cell. 2005;120:159–62.

    CAS  PubMed  Google Scholar 

  14. B’Chir W, Maurin AC, Carraro V, Averous J, Jousse C, Muranishi Y, et al. The eIF2alpha/ATF4 pathway is essential for stress-induced autophagy gene expression. Nucleic Acids Res. 2013;41:7683–99.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Son Y, Cheong YK, Kim NH, Chung HT, Kang DG, Pae HO. Mitogen-activated protein kinases and reactive oxygen species: how can ROS activate MAPK pathways?J Signal Transduct. 2011;2011:792639.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Oberstein A, Jeffrey PD, Shi Y. Crystal structure of the Bcl-XL-Beclin 1 peptide complex: Beclin 1 is a novel BH3-only protein. J Biol Chem. 2007;282:13123–32.

    Article  CAS  PubMed  Google Scholar 

  17. Liang XH, Kleeman LK, Jiang HH, Gordon G, Goldman JE, Berry G, et al. Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J Virol. 1998;72:8586–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Filomeni G, De Zio D, Cecconi F. Oxidative stress and autophagy: the clash between damage and metabolic needs. Cell Death Differ. 2015;22:377–88.

    Article  CAS  PubMed  Google Scholar 

  19. Kroemer G, Mariño G, Levine B. Autophagy and the integrated stress response. Mol Cell. 2010;40:280–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Dibble CC, Manning BD. Signal integration by mTORC1 coordinates nutrient input with biosynthetic output. Nat Cell Biol. 2013;15:555–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol. 2011;13:132–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Inoki K, Li Y, Zhu T, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol. 2002;4:648–57.

    Article  CAS  PubMed  Google Scholar 

  23. Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell. 2010;141:290–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Russell RC, Yuan H-X, Guan K-L. Autophagy regulation by nutrient signaling. Cell Res. 2014;24:42–57.

    Article  CAS  PubMed  Google Scholar 

  25. Mitchener JS, Shelburne JD, Bradford WD, Hawkins HK. Cellular autophagocytosis induced by deprivation of serum and amino acids in HeLa cells. Am J Pathol. 1976;83:485–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Mortimore GE, Schworer CM. Induction of autophagy by amino-acid deprivation in perfused rat liver. Nature. 1977;270:174–6.

    Article  CAS  PubMed  Google Scholar 

  27. Noda T, Ohsumi Y. Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem. 1998;273:3963–6.

    Article  CAS  PubMed  Google Scholar 

  28. Scott RC, Schuldiner O, Neufeld TP. Role and regulation of starvation-induced autophagy in the Drosophila fat body. Dev Cell. 2004;7:167–78.

    Article  CAS  PubMed  Google Scholar 

  29. Gallagher LE, Chan EY. Early signalling events of autophagy. Essays Biochem. 2013;55:1–15.

    Article  PubMed  Google Scholar 

  30. Tooze SA, Yoshimori T. The origin of the autophagosomal membrane. Nat Cell Biol. 2010;12:831–5.

    Article  CAS  PubMed  Google Scholar 

  31. Simonsen A, Tooze SA. Coordination of membrane events during autophagy by multiple class III PI3-kinase complexes. J Cell Biol. 2009;186:773–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lamb CA, Yoshimori T, Tooze SA. The autophagosome: origins unknown, biogenesis complex. Nat Rev Mol Cell Biol. 2013;14:759–74.

    Article  CAS  PubMed  Google Scholar 

  33. Nakatogawa H. Two ubiquitin-like conjugation systems that mediate membrane formation during autophagy. Essays Biochem. 2013;55:39–50.

    Article  CAS  PubMed  Google Scholar 

  34. Fujita N, Itoh T, Omori H, Fukuda M, Noda T, Yoshimori T. The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy. Mol Biol Cell. 2008;19:2092–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Dooley HC, Razi M, Polson HE, Girardin SE, Wilson MI, Tooze SA. WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12-5-16L1. Mol Cell. 2014;55:238–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Satoo K, Noda NN, Kumeta H, Fujioka Y, Mizushima N, Ohsumi Y, et al. The structure of Atg4B-LC3 complex reveals the mechanism of LC3 processing and delipidation during autophagy. EMBO J. 2009;28:1341–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Schaaf MB, Keulers TG, Vooijs MA, Rouschop KM. LC3/GABARAP family proteins: autophagy-(un)related functions. FASEB J. 2016;30:3961–78.

    Article  CAS  PubMed  Google Scholar 

  38. Tanida I, Ueno T, Kominami E. LC3 conjugation system in mammalian autophagy. Int J Biochem Cell Biol. 2004;36:2503–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ganley IG. Autophagosome maturation and lysosomal fusion. Essays Biochem. 2013;55:65–78.

    Article  CAS  PubMed  Google Scholar 

  40. Eskelinen E-L. Maturation of autophagic vacuoles in mammalian cells. Autophagy. 2004;1:1–10.

    Article  Google Scholar 

  41. Gutierrez MG, Munafó DB, Berón W, Colombo MI. Rab7 is required for the normal progression of the autophagic pathway in mammalian cells. J Cell Sci. 2004;117:2687–97.

    Article  CAS  PubMed  Google Scholar 

  42. Itakura E, Kishi-Itakura C, Mizushima N. The hairpin-type tail-anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes. Cell. 2012;151:1256–69.

    Article  CAS  PubMed  Google Scholar 

  43. Jiang P, Nishimura T, Sakamaki Y, Itakura E, Hatta T, Natsume T, et al. The HOPS complex mediates autophagosome–lysosome fusion through interaction with syntaxin 17. Mol Biol Cell. 2014;25:1327–37.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Boya P, Gonzalez-Polo RA, Casares N, Perfettini JL, Dessen P, Larochette N, et al. Inhibition of macroautophagy triggers apoptosis. Mol Cell Biol. 2005;25:1025–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yamamoto A, Tagawa Y, Yoshimori T, Moriyama Y, Masaki R, Tashiro Y. 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.

    Article  CAS  PubMed  Google Scholar 

  46. Doi S, Tanabe K, Watanabe M, Yoshimura M. Chloroquine, a lysosomotropic agent, inhibits zygote formation in yeast. Arch Microbiol. 1989;151:20–25.

    Article  CAS  PubMed  Google Scholar 

  47. Mauvezin C, Neufeld TP. Bafilomycin A1 disrupts autophagic flux by inhibiting both V-ATPase-dependent acidification and Ca-P60A/SERCA-dependent autophagosome-lysosome fusion. Autophagy. 2015;11:1437–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Eskelinen EL, Tanaka Y, Saftig P. At the acidic edge: emerging functions for lysosomal membrane proteins. Trends Cell Biol. 2003;13:137–45.

    Article  CAS  PubMed  Google Scholar 

  49. Khaminets A, Behl C, Dikic I. Ubiquitin-dependent and independent signals in selective autophagy. Trends Cell Biol. 2016;26:6–16.

    Article  CAS  PubMed  Google Scholar 

  50. Stolz A, Ernst A, Dikic I. Cargo recognition and trafficking in selective autophagy. Nat Cell Biol. 2014;16:495–501.

    Article  CAS  PubMed  Google Scholar 

  51. Settembre C, Di Malta C, Polito VA, Garcia Arencibia M, Vetrini F, Erdin S, et al. TFEB links autophagy to lysosomal biogenesis. Science. 2011;332:1429–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Chauhan S, Goodwin JG, Chauhan S, Manyam G, Wang J, Kamat AM, et al. ZKSCAN3 is a master transcriptional repressor of autophagy. Mol Cell. 2013;50:16–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Fullgrabe J, Klionsky DJ, Joseph B. The return of the nucleus: transcriptional and epigenetic control of autophagy. Nat Rev Mol Cell Biol. 2014;15:65–74.

    Article  PubMed  CAS  Google Scholar 

  54. Shin HJ, Kim H, Oh S, Lee JG, Kee M, Ko HJ, et al. AMPK-SKP2-CARM1 signalling cascade in transcriptional regulation of autophagy. Nature. 2016;534:553–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Selvi BR, Batta K, Kishore AH, Mantelingu K, Varier RA, Balasubramanyam K, et al. Identification of a novel inhibitor of coactivator-associated arginine methyltransferase 1 (CARM1)-mediated methylation of histone H3 Arg-17. J Biol Chem. 2010;285:7143–52.

    Article  CAS  PubMed  Google Scholar 

  56. Fullgrabe J, Lynch-Day MA, Heldring N, Li W, Struijk RB, Ma Q, et al. The histone H4 lysine 16 acetyltransferase hMOF regulates the outcome of autophagy. Nature. 2013;500:468–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Huang R, Xu Y, Wan W, Shou X, Qian J, You Z et al. Deacetylation of nuclear LC3 drives autophagy initiation under starvation. Mol Cell. 2015;57:456–66.

    Article  CAS  PubMed  Google Scholar 

  58. Artal-Martinez de Narvajas A, Gomez TS, Zhang JS, Mann AO, Taoda Y, Gorman JA, et al. Epigenetic regulation of autophagy by the methyltransferase G9a. Mol Cell Biol. 2013;33:3983–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Wei F-Z, Cao Z, Wang X, Wang H, Cai M-Y, Li T, et al. Epigenetic regulation of autophagy by the methyltransferase EZH2 through an MTOR-dependent pathway. Autophagy. 2015;11:2309–22.

    Article  CAS  PubMed  Google Scholar 

  60. Eisenberg-Lerner A, Kimchi A. The paradox of autophagy and its implication in cancer etiology and therapy. Apoptosis. 2009;14:376–91.

    Article  PubMed  Google Scholar 

  61. White E. Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer. 2012;12:401–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Yang ZJ, Chee CE, Huang S, Sinicrope FA. The role of autophagy in cancer: therapeutic implications. Mol Cancer Ther. 2011;10:1533–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Kung CP, Budina A, Balaburski G, Bergenstock MK, Murphy M. Autophagy in tumor suppression and cancer therapy. Crit Rev Eukaryot Gene Expr. 2011;21:71–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature. 1999;402:672–6.

    Article  CAS  PubMed  Google Scholar 

  65. Shen Y, Li DD, Wang LL, Deng R, Zhu XF. Decreased expression of autophagy-related proteins in malignant epithelial ovarian cancer. Autophagy. 2008;4:1067–8.

    Article  CAS  PubMed  Google Scholar 

  66. Furuya N, Yu J, Byfield M, Pattingre S, Levine B. The evolutionarily conserved domain of Beclin 1 is required for Vps34 binding, autophagy and tumor suppressor function. Autophagy. 2005;1:46–52.

    Article  CAS  PubMed  Google Scholar 

  67. Takahashi Y, Coppola D, Matsushita N, Cualing HD, Sun M, Sato Y, et al. Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat Cell Biol. 2007;9:1142–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Takamura A, Komatsu M, Hara T, Sakamoto A, Kishi C, Waguri S, et al. Autophagy-deficient mice develop multiple liver tumors. Genes Dev. 2011;25:795–800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Kimmelman AC. The dynamic nature of autophagy in cancer. Genes Dev. 2011;25:1999–2010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Noguchi M, Hirata N, Suizu F. The links between AKT and two intracellular proteolytic cascades: ubiquitination and autophagy. Biochim Biophys Acta. 2014;1846:342–52.

    CAS  PubMed  Google Scholar 

  71. Roy S, Debnath J. Autophagy and tumorigenesis. Semin Immunopathol. 2010;32:383–96.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Errafiy R, Aguado C, Ghislat G, Esteve JM, Gil A, Loutfi M, et al. PTEN increases autophagy and inhibits the ubiquitin-proteasome pathway in glioma cells independently of its lipid phosphatase activity. PLoS ONE. 2013;8:e83318.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Mathew R, Karp CM, Beaudoin B, Vuong N, Chen G, Chen HY et al. Autophagy suppresses tumorigenesis through elimination of p62. Cell. 2009;137:1062–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Liu EY, Ryan KM. Autophagy and cancer – issues we need to digest. J Cell Sci. 2012;125:2349–58.

    PubMed  Google Scholar 

  75. Wei H, Wei S, Gan B, Peng X, Zou W, Guan J-L. Suppression of autophagy by FIP200 deletion inhibits mammary tumorigenesis. Genes Dev. 2011;25:1510–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Kim M-J, Woo S-J, Yoon C-H, Lee J-S, An S, Choi Y-H, et al. Involvement of autophagy in oncogenic K-Ras-induced malignant cell transformation. J Biol Chem. 2011;286:12924–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Yang S, Wang X, Contino G, Liesa M, Sahin E, Ying H, et al. Pancreatic cancers require autophagy for tumor growth. Genes Dev. 2011;25:717–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000; 100: 57–70.

    Article  CAS  PubMed  Google Scholar 

  79. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144:646–74.

    Article  CAS  PubMed  Google Scholar 

  80. Yang ZJ, Chee CE, Huang S, Sinicrope FA. The role of autophagy in cancer: therapeutic implications. Mol Cancer Ther. 2011;10:1533–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Cianfanelli V, Fuoco C, Lorente M, Salazar M, Quondamatteo F, Gherardini PF, et al. AMBRA1 links autophagy to cell proliferation and tumorigenesis by promoting c-Myc dephosphorylation and degradation. Nat Cell Biol. 2015;17:706.

    Article  CAS  PubMed  Google Scholar 

  82. Guo JY, Karsli-Uzunbas G, Mathew R, Aisner SC, Kamphorst JJ, Strohecker AM, et al. Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis. Genes Dev. 2013;27:1447–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Chatterjee A, Mukhopadhyay S, Tung K, Patel D, Foster DA. Rapamycin-induced G1 cell cycle arrest employs both TGF-β and Rb pathways. Cancer Lett. 2015;360:134–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Yazbeck VY, Buglio D, Georgakis GV, Li Y, Iwado E, Romaguera JE, et al. Temsirolimus downregulates p21 without altering cyclin D1 expression and induces autophagy and synergizes with vorinostat in mantle cell lymphoma. Exp Hematol. 2008;36:443–50.

    Article  CAS  PubMed  Google Scholar 

  85. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003;3:401–10.

    Article  CAS  PubMed  Google Scholar 

  86. Cavallaro U, Christofori G. Molecular mechanisms of tumor angiogenesis and tumor progression. J Neurooncol. 2000;50:63–70.

    Article  CAS  PubMed  Google Scholar 

  87. Meadows KL, Hurwitz HI. Anti-VEGF therapies in the clinic. Cold Spring Harb Perspect Med. 2012;2.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Hu YL, DeLay M, Jahangiri A, Molinaro AM, Rose SD, Carbonell WS, et al. Hypoxia-induced autophagy promotes tumor cell survival and adaptation to antiangiogenic treatment in glioblastoma. Cancer Res. 2012;72:1773–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Nishikawa T, Tsuno NH, Okaji Y, Sunami E, Shuno Y, Sasaki K, et al. The inhibition of autophagy potentiates anti-angiogenic effects of sulforaphane by inducing apoptosis. Angiogenesis. 2010;13:227–38.

    Article  CAS  PubMed  Google Scholar 

  90. Ramakrishnan S, Nguyen TM, Subramanian IV, Kelekar A. Autophagy and angiogenesis inhibition. Autophagy. 2007;3:512–5.

    Article  CAS  PubMed  Google Scholar 

  91. Kim KW, Paul P, Qiao J, Lee S, Chung DH. Enhanced autophagy blocks angiogenesis via degradation of gastrin-releasing peptide in neuroblastoma cells. Autophagy. 2013;9:1579–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Kenific CM, Thorburn A, Debnath J. Autophagy and metastasis: another double-edged sword. Curr Opin Cell Biol. 2010;22:241–5.

    Article  CAS  PubMed  Google Scholar 

  93. Qiang L, Zhao B, Ming M, Wang N, He TC, Hwang S, et al. Regulation of cell proliferation and migration by p62 through stabilization of Twist1. Proc Natl Acad Sci USA. 2014;111:9241–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Gilmore AP. Anoikis. Cell Death Differ. 2005;12(Suppl 2):1473–7.

    Article  CAS  PubMed  Google Scholar 

  95. Guadamillas MC, Cerezo A, Del Pozo MA. Overcoming anoikis--pathways to anchorage-independent growth in cancer. J Cell Sci. 2011;124:3189–97.

    Article  CAS  PubMed  Google Scholar 

  96. Li J, Yang B, Zhou Q, Wu Y, Shang D, Guo Y, et al. Autophagy promotes hepatocellular carcinoma cell invasion through activation of epithelial-mesenchymal transition. Carcinogenesis. 2013;34:1343–51.

    Article  CAS  PubMed  Google Scholar 

  97. Zhai H, Fesler A, Ba Y, Wu S, Ju J. Inhibition of colorectal cancer stem cell survival and invasive potential by hsa-miR-140-5p mediated suppression of Smad2 and autophagy. Oncotarget. 2015;6:19735–46.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Lane DP. Cancer. p53, guardian of the genome. Nature. 1992;358:15–16.

    Article  CAS  PubMed  Google Scholar 

  99. Fernald K, Kurokawa M. Evading apoptosis in cancer. Trends Cell Biol. 2013;23:620–33.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Hanahan D, Weinberg Robert A. Hallmarks of cancer: The next generation. Cell. 2011;144:646-74.

    Article  CAS  PubMed  Google Scholar 

  101. Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell. 2005;122:927–39.

    Article  CAS  PubMed  Google Scholar 

  102. Levine B, Yuan J. Autophagy in cell death: an innocent convict? J Clin Invest 2005;115:2679–88.

    Article  CAS  Google Scholar 

  103. Josset E, Burckel H, Noel G, Bischoff P. The mTOR inhibitor RAD001 potentiates autophagic cell death induced by temozolomide in a glioblastoma cell line. Anticancer Res. 2013;33:1845–51.

    CAS  PubMed  Google Scholar 

  104. Kanzawa T, Kondo Y, Ito H, Kondo S, Germano I. Induction of autophagic cell death in malignant glioma cells by arsenic trioxide. Cancer Res. 2003;63:2103–8.

    CAS  PubMed  Google Scholar 

  105. Kohli L, Kaza N, Coric T, Byer SJ, Brossier NM, Klocke BJ, et al. 4-Hydroxytamoxifen induces autophagic death through K-Ras degradation. Cancer Res. 2013;73:4395–405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Salazar M, Carracedo A, Salanueva IJ, Hernandez-Tiedra S, Lorente M, Egia A, et al. Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. J Clin Invest. 2009;119:1359–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell. 2012;21:297–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. White E. Exploiting the bad eating habits of Ras-driven cancers. Genes Dev. 2013;27:2065–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Kenific CM, Debnath J. Cellular and metabolic functions for autophagy in cancer cells. Trends Cell Biol. 2015;25:37–45.

    Article  CAS  PubMed  Google Scholar 

  110. Cook KL, Shajahan AN, Clarke R. Autophagy and endocrine resistance in breast cancer. Expert Rev Anticancer Ther. 2011;11:1283–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Jain K, Paranandi KS, Sridharan S, Basu A. Autophagy in breast cancer and its implications for therapy. Am J Cancer Res. 2013;3:251–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Wang J, Wu GS. Role of autophagy in cisplatin resistance in ovarian cancer cells. J Biol Chem. 2014;289:17163–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Sui X, Chen R, Wang Z, Huang Z, Kong N, Zhang M, et al. Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment. Cell Death Dis. 2013;4:e838.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Y-p Yang, L-f Hu, H-f Zheng, C-j Mao, W-d Hu, K-p Xiong, et al. Application and interpretation of current autophagy inhibitors and activators. Acta Pharmacol Sin. 2013;34:625–35.

    Article  CAS  Google Scholar 

  115. Song J, Qu Z, Guo X, Zhao Q, Zhao X, Gao L, et al. Hypoxia-induced autophagy contributes to the chemoresistance of hepatocellular carcinoma cells. Autophagy. 2009;5:1131–44.

    Article  CAS  PubMed  Google Scholar 

  116. Selvakumaran M, Amaravadi RK, Vasilevskaya IA, O’Dwyer PJ. Autophagy inhibition sensitizes colon cancer cells to antiangiogenic and cytotoxic therapy. Clin Cancer Res. 2013;19:2995–3007.

    Article  CAS  PubMed  Google Scholar 

  117. Crazzolara R, Cisterne A, Thien M, Hewson J, Baraz R, Bradstock KF, et al. Potentiating effects of RAD001 (Everolimus) on vincristine therapy in childhood acute lymphoblastic leukemia. Blood. 2009;113:3297–306.

    Article  CAS  PubMed  Google Scholar 

  118. Milano V, Piao Y, LaFortune T, de Groot J. Dasatinib-induced autophagy is enhanced in combination with temozolomide in glioma. Mol Cancer Ther. 2009;8:394–406.

    Article  CAS  PubMed  Google Scholar 

  119. Liu YL, Yang PM, Shun CT, Wu MS, Weng JR, Chen CC. Autophagy potentiates the anti-cancer effects of the histone deacetylase inhibitors in hepatocellular carcinoma. Autophagy. 2010;6:1057–65.

    Article  CAS  PubMed  Google Scholar 

  120. Shao Y, Gao Z, Marks PA, Jiang X. Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. Proc Natl Acad Sci USA. 2004;101:18030–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med. 2002;8:128–35.

    Article  CAS  PubMed  Google Scholar 

  122. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372:449–56.

    Article  CAS  PubMed  Google Scholar 

  123. Copeland RA, Solomon ME, Richon VM. Protein methyltransferases as a target class for drug discovery. Nat Rev Drug Discov. 2009;8:724–32.

    Article  CAS  PubMed  Google Scholar 

  124. Chung YC, Lu LC, Tsai MH, Chen YJ, Chen YY, Yao SP, et al. The inhibitory effect of ellagic acid on cell growth of ovarian carcinoma cells. Evid Based Complement Altern Med. 2013;2013:306705.

    Google Scholar 

  125. Hsieh YY, Lo HL, Yang PM. EZH2 inhibitors transcriptionally upregulate cytotoxic autophagy and cytoprotective unfolded protein response in human colorectal cancer cells. Am J Cancer Res. 2016;6:1661–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. He S, Zhao Z, Yang Y, O’Connell D, Zhang X, Oh S, et al. Truncating mutation in the autophagy gene UVRAG confers oncogenic properties and chemosensitivity in colorectal cancers. Nat Commun. 2015;6:7839.

    Article  CAS  PubMed  Google Scholar 

  127. Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61–70.

    Article  CAS  Google Scholar 

  128. Cancer Genome Atlas N. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330–7.

    Article  CAS  Google Scholar 

  129. Cancer Genome Atlas N. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474:609–15.

    Article  CAS  Google Scholar 

  130. Cancer Genome Atlas N. Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012;489:519–25.

    Article  CAS  Google Scholar 

  131. Cancer Genome Atlas N. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511:543–50.

    Article  CAS  Google Scholar 

  132. Cancer Genome Atlas N. The molecular taxonomy of primary prostate. Cancer Cell. 2015;163:1011–25.

    Google Scholar 

  133. Rebecca VW, Amaravadi RK. Emerging strategies to effectively target autophagy in cancer. Oncogene. 2016;35:1–11.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

APK was supported by grants from National Medical Research Council of Singapore, NCIS Yong Siew Yoon Research Grant through donations from the Yong Loo Lin Trust and by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centers of Excellence initiative to Cancer Science Institute of Singapore, National University of Singapore. This work was also supported by Wellcome Trust/DBT India Alliance Intermediate Fellowship (509159/Z/09/Z) and JNCASR intramural funds to RM. The JNCASR doctoral fellowship to SV is also acknowledged. We also thank Dr. Prathibha Ranganathan (Centre for Human Genetics, Bengaluru), Aparna Hebbar and members of Autophagy lab (JNCASR) for critical reading of the manuscript. This work was supported by NUHS Basic seed grant [T1-BSRG 2015-02] and Ministry of Education Tier 1 grant to GS. The John Nott Cancer Fellowship from Cancer Council, Western Australia also supported GS. This work is supported in part by National Medical Research Council Singapore (NMRC) grants (NMRC-CIRG/1346/2012 and NMRC/CIRG/1373/2013) to HMS.

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Shikha Satendra Singh and Somya Vats contributed equally to this work.

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Singh, S.S., Vats, S., Chia, A.YQ. et al. Dual role of autophagy in hallmarks of cancer. Oncogene 37, 1142–1158 (2018). https://doi.org/10.1038/s41388-017-0046-6

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