Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Emerging strategies to effectively target autophagy in cancer

Oncogene volume 35, pages 1–11 (2016)Cite this article

Subjects

Abstract

Autophagy serves a dichotomous role in cancer and recent advances have helped delineate the appropriate settings where inhibiting or promoting autophagy may confer therapeutic efficacy in patients. Our evolving understanding of the molecular machinery responsible for the tightly controlled regulation of this homeostatic mechanism has begun to bear fruit in the way of autophagy-oriented clinical trials and promising lead compounds to modulate autophagy for therapeutic benefit. In this manuscript we review the recent preclinical and clinical therapeutic strategies that involve autophagy modulation in cancer.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Zou CG, Ma YC, Dai LL, Zhang KQ . Autophagy protects C. elegans against necrosis during Pseudomonas aeruginosa infection. Proc Natl Acad Sci USA 2014; 111: 12480–12485.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Chen M, Hong MJ, Sun H, Wang L, Shi X, Gilbert BE et al. Essential role for autophagy in the maintenance of immunological memory against influenza infection. Nat Med 2014; 20: 503–510.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Deretic V . Autophagy in tuberculosis. Cold Spring Harb Perspect Med 2014; 4: a018481.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Xu X, Araki K, Li S, Han JH, Ye L, Tan WG et al. Autophagy is essential for effector CD8(+) T cell survival and memory formation. Nature Immunol 2014; 15: 1152–1161.

    Article  CAS  Google Scholar 

  5. Rao S, Yang H, Penninger JM, Kroemer G . Autophagy in non-small cell lung carcinogenesis: a positive regulator of antitumor immunosurveillance. Autophagy 2014; 10: 529–531.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wong YC, Holzbaur EL . Optineurin is an autophagy receptor for damaged mitochondria in parkin-mediated mitophagy that is disrupted by an ALS-linked mutation. Proc Natl Acad Sci USA 2014; 111: E4439–E4448.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. McLendon PM, Ferguson BS, Osinska H, Bhuiyan MS, James J, McKinsey TA et al. Tubulin hyperacetylation is adaptive in cardiac proteotoxicity by promoting autophagy. Proc Natl Acad Sci USA 2014; 111: E5178–E5186.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Amaravadi RK, Lippincott-Schwartz J, Yin XM, Weiss WA, Takebe N, Timmer W et al. Principles and current strategies for targeting autophagy for cancer treatment. Clin Cancer Res 2011; 17: 654–666.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hanahan D, Weinberg RA . Hallmarks of cancer: the next generation. Cell 2011; 144: 646–674.

    Article  CAS  PubMed  Google Scholar 

  10. Galluzzi L, Pietrocola F, Levine B, Kroemer G . Metabolic Control of autophagy. Cell 2014; 159: 1263–1276.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Amaravadi RK, Thompson CB . The roles of therapy-induced autophagy and necrosis in cancer treatment. Clin Cancer Res 2007; 13: 7271–7279.

    Article  CAS  PubMed  Google Scholar 

  12. Barnard RA, Wittenburg LA, Amaravadi RK, Gustafson DL, Thorburn A, Thamm DH . Phase I clinical trial and pharmacodynamic evaluation of combination hydroxychloroquine and doxorubicin treatment in pet dogs treated for spontaneously occurring lymphoma. Autophagy 2014; 10: 1415–1425.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mahalingam D, Mita M, Sarantopoulos J, Wood L, Amaravadi RK, Davis LE et al. Combined autophagy and HDAC inhibition: a phase I safety, tolerability, pharmacokinetic, and pharmacodynamic analysis of hydroxychloroquine in combination with the HDAC inhibitor vorinostat in patients with advanced solid tumors. Autophagy 2014; 10: 1403–1414.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Rangwala R, Chang YC, Hu J, Algazy KM, Evans TL, Fecher LA et al. Combined MTOR and autophagy inhibition: phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma. Autophagy 2014; 10: 1391–1402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Rangwala R, Leone R, Chang YC, Fecher LA, Schuchter LM, Kramer A et al. Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma. Autophagy 2014; 10: 1369–1379.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Rosenfeld MR, Ye X, Supko JG, Desideri S, Grossman SA, Brem S et al. A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme. Autophagy 2014; 10: 1359–1368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Vogl DT, Stadtmauer EA, Tan KS, Heitjan DF, Davis LE, Pontiggia L et al. Combined autophagy and proteasome inhibition: a phase 1 trial of hydroxychloroquine and bortezomib in patients with relapsed/refractory myeloma. Autophagy 2014; 10: 1380–1390.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wolpin BM, Rubinson DA, Wang X, Chan JA, Cleary JM, Enzinger PC et al. Phase II and pharmacodynamic study of autophagy inhibition using hydroxychloroquine in patients with metastatic pancreatic adenocarcinoma. Oncologist 2014; 19: 637–638.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Takeshige K, Baba M, Tsuboi S, Noda T, Ohsumi Y . Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction. J Cell Biol 1992; 119: 301–311.

    Article  CAS  PubMed  Google Scholar 

  20. Choi AMK, Ryter SW, Levine B . Autophagy in Human Health and Disease. N Engl J Med 2013; 368: 651–662.

    Article  CAS  PubMed  Google Scholar 

  21. Lum JJ, Bauer DE, Kong M, Harris MH, Li C, Lindsten T et al. Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell 2005; 120: 237–248.

    Article  CAS  PubMed  Google Scholar 

  22. Wu H, Xue D, Chen G, Han Z, Huang L, Zhu C et al. The BCL2L1 and PGAM5 axis defines hypoxia-induced receptor-mediated mitophagy. Autophagy 2014; 10: 1712–1725.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ma XH, Piao SF, Dey S, McAfee Q, Karakousis G, Villanueva J et al. Targeting ER stress-induced autophagy overcomes BRAF inhibitor resistance in melanoma. J Clin Invest 2014; 124: 1406–1417.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Klionsky DJ, Codogno P, Cuervo AM, Deretic V, Elazar Z, Fueyo-Margareto J et al. A comprehensive glossary of autophagy-related molecules and processes. Autophagy 2010; 6: 438–448.

    Article  PubMed  Google Scholar 

  25. Wang K, Klionsky DJ . Mitochondria removal by autophagy. Autophagy 2011; 7: 297–300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tanida I . Autophagosome formation and molecular mechanism of autophagy. Antioxid Redox Signal 2011; 14: 2201–2214.

    Article  CAS  PubMed  Google Scholar 

  27. Cecconi F, Di Bartolomeo S, Nardacci R, Fuoco C, Corazzari M, Giunta L et al. A novel role for autophagy in neurodevelopment. Autophagy 2007; 3: 506–508.

    Article  CAS  PubMed  Google Scholar 

  28. Codogno P, Mehrpour M, Proikas-Cezanne T . Canonical and non-canonical autophagy: variations on a common theme of self-eating? Nat Rev Mol Cell Biol 2012; 13: 7–12.

    Article  CAS  Google Scholar 

  29. Kishi-Itakura C, Koyama-Honda I, Itakura E, Mizushima N . Ultrastructural analysis of autophagosome organization using mammalian autophagy-deficient cells. J Cell Sci 2014; 127 (Pt 18): 4089–4102.

    CAS  PubMed  Google Scholar 

  30. Mathew R, White E . Autophagy, stress, and cancer metabolism: what doesn't kill you makes you stronger. Cold Spring Harb Symp Quant Biol 2011; 76: 389–396.

    Article  CAS  PubMed  Google Scholar 

  31. Kim J, Kundu M, Viollet B, Guan KL . AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nature Cell Biol 2011; 13: 132–141.

    Article  CAS  PubMed  Google Scholar 

  32. Marino G, Niso-Santano M, Baehrecke EH, Kroemer G . Self-consumption: the interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol 2014; 15: 81–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wong PM, Puente C, Ganley IG, Jiang X . The ULK1 complex: sensing nutrient signals for autophagy activation. Autophagy 2013; 9: 124–137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mandell MA, Jain A, Arko-Mensah J, Chauhan S, Kimura T, Dinkins C et al. TRIM proteins regulate autophagy and can target autophagic substrates by direct recognition. Dev Cell 2014; 30: 394–409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Backer JM . The regulation and function of Class III PI3Ks: novel roles for Vps34. Biochem J 2008; 410: 1–17.

    Article  CAS  PubMed  Google Scholar 

  36. Hayashi-Nishino M, Fujita N, Noda T, Yamaguchi A, Yoshimori T, Yamamoto A . A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Nat Cell Biol 2009; 11: 1433–1437.

    Article  CAS  PubMed  Google Scholar 

  37. Ravikumar B, Moreau K, Jahreiss L, Puri C, Rubinsztein DC . Plasma membrane contributes to the formation of pre-autophagosomal structures. Nat Cell Biol 2010; 12: 747–757.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hailey DW, Rambold AS, Satpute-Krishnan P, Mitra K, Sougrat R, Kim PK et al. Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell 2010; 141: 656–667.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Nishida Y, Arakawa S, Fujitani K, Yamaguchi H, Mizuta T, Kanaseki T et al. Discovery of Atg5/Atg7-independent alternative macroautophagy. Nature 2009; 461: 654–658.

    Article  CAS  PubMed  Google Scholar 

  40. Ravikumar B, Imarisio S, Sarkar S, O'Kane CJ, Rubinsztein DC . Rab5 modulates aggregation and toxicity of mutant huntingtin through macroautophagy in cell and fly models of Huntington disease. J Cell Sci 2008; 121 (Pt 10): 1649–1660.

    Article  CAS  PubMed  Google Scholar 

  41. Rothe K, Lin H, Lin KB, Leung A, Wang HM, Malekesmaeili M et al. The core autophagy protein ATG4B is a potential biomarker and therapeutic target in CML stem/progenitor cells. Blood 2014; 123: 3622–3634.

    Article  CAS  PubMed  Google Scholar 

  42. Fujita K, Maeda D, Xiao Q, Srinivasula SM . Nrf2-mediated induction of p62 controls Toll-like receptor-4-driven aggresome-like induced structure formation and autophagic degradation. Proc Natl Acad Sci USA 2011; 108: 1427–1432.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Behrends C, Sowa ME, Gygi SP, Harper JW . Network organization of the human autophagy system. Nature 2010; 466: 68–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Mijaljica D, Prescott M, Devenish RJ . V-ATPase engagement in autophagic processes. Autophagy 2011; 7: 666–668.

    Article  CAS  PubMed  Google Scholar 

  45. Rong Y, McPhee CK, Deng S, Huang L, Chen L, Liu M et al. Spinster is required for autophagic lysosome reformation and mTOR reactivation following starvation. Proc Natl Acad Sci USA 2011; 108: 7826–7831.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Mathew R, Karp CM, Beaudoin B, Vuong N, Chen G, Chen HY et al. Autophagy suppresses tumorigenesis through elimination of p62. Cell 2009; 137: 1062–1075.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Yue Z, Jin S, Yang C, Levine AJ, Heintz N . Beclin 1. An autophagy gene essential for early embryonic development, is a haplosufficient tumor suppressor. Proc Natl Acad Sci USA 2003; 100: 15077–15082.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest 2003; 112: 1809–1820.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Laddha SV, Ganesan S, Chan CS, White E . Mutational landscape of the essential autophagy gene BECN1 in human cancers. Mol Cancer Res 2014; 12: 485–490.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Liu J, Xia H, Kim M, Xu L, Li Y, Zhang L et al. Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13. Cell 2011; 147: 223–234.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Elgendy M, Ciro M, Abdel-Aziz AK, Belmonte G, Zuffo RD, Mercurio C et al. Beclin 1 restrains tumorigenesis through Mcl-1 destabilization in an autophagy-independent reciprocal manner. Nat Commun 2014; 5: 5637.

    Article  CAS  PubMed  Google Scholar 

  52. Wei Y, Zou Z, Becker N, Anderson M, Sumpter R, Xiao G et al. EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance. Cell 2013; 154: 1269–1284.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 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 

  54. Wei H, Wang C, Croce CM, Guan JL . p62/SQSTM1 synergizes with autophagy for tumor growth in vivo Genes Dev 2014; 28: 1204–1216.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Wei H, Wei S, Gan B, Peng X, Zou W, Guan JL . Suppression of autophagy by FIP200 deletion inhibits mammary tumorigenesis. Genes Dev 2011; 25: 1510–1527.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 2006; 10: 51–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ma XH, Piao S, Wang D, McAfee QW, Nathanson KL, Lum JJ et al. Measurements of tumor cell autophagy predict invasiveness, resistance to chemotherapy, and survival in melanoma. Clin Cancer Res 2011; 17: 3478–3489.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 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: 1447–1461.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Rao S, Tortola L, Perlot T, Wirnsberger G, Novatchkova M, Nitsch R et al. A dual role for autophagy in a murine model of lung cancer. Nat Commun 2014; 5: 3056.

    Article  PubMed  CAS  Google Scholar 

  60. Strohecker AM, Guo JY, Karsli-Uzunbas G, Price SM, Chen GJ, Mathew R et al. Autophagy sustains mitochondrial glutamine metabolism and growth of BrafV600E-driven lung tumors. Cancer Discov 2013; 3: 1272–1285.

    Article  CAS  PubMed  Google Scholar 

  61. 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: 717–729.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Viale A, Pettazzoni P, Lyssiotis CA, Ying H, Sanchez N, Marchesini M et al. Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature 2014; 514: 628–632.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Karsli-Uzunbas G, Guo JY, Price S, Teng X, Laddha SV, Khor S et al. Autophagy is required for glucose homeostasis and lung tumor maintenance. Cancer Discov 2014; 4: 914–927.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Rosenfeldt MT, O'Prey J, Morton JP, Nixon C, MacKay G, Mrowinska A et al. p53 status determines the role of autophagy in pancreatic tumour development. Nature 2013; 504: 296–300.

    Article  CAS  PubMed  Google Scholar 

  65. Amaravadi R, Debnath J . Mouse models address key concerns regarding autophagy inhibition in cancer therapy. Cancer Discov 2014; 4: 873–875.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB, Hruban RH et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 2005; 7: 469–483.

    Article  CAS  PubMed  Google Scholar 

  67. Yang A, Rajeshkumar NV, Wang X, Yabuuchi S, Alexander BM, Chu GC et al. Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations. Cancer Discov 2014; 4: 905–913.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Iacobuzio-Donahue CA, Herman JM . Autophagy, p53, and pancreatic cancer. N Engl J Med 2014; 370: 1352–1353.

    Article  CAS  PubMed  Google Scholar 

  69. Fulda S, Kogel D . Cell death by autophagy: emerging molecular mechanisms and implications for cancer therapy. Oncogene; e-pub ahead of print 26 January 2015; doi:10.1038/onc.2014.458.

    Article  CAS  PubMed  Google Scholar 

  70. Galluzzi L, Vitale I, Abrams JM, Alnemri ES, Baehrecke EH, Blagosklonny MV et al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ 2012; 19: 107–120.

    Article  CAS  PubMed  Google Scholar 

  71. Galluzzi L, Bravo-San Pedro JM, Vitale I, Aaronson SA, Abrams JM, Adam D et al. Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ 2015; 22: 58–73.

    Article  CAS  PubMed  Google Scholar 

  72. Yu L, Alva A, Su H, Dutt P, Freundt E, Welsh S . Reguation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 2004; 304: 1500–1502.

    Article  CAS  PubMed  Google Scholar 

  73. Lu Z, Luo RZ, Lu Y, Zhang X, Yu Q, Khare S et al. The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human ovarian cancer cells. J Clin Invest 2008; 118: 3917–3929.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Michaud M, Martins I, Sukkurwala AQ, Adjemian S, Ma Y, Pellegatti P et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 2011; 334: 1573–1577.

    Article  CAS  PubMed  Google Scholar 

  75. Ramakrishnan R, Huang C, Cho HI, Lloyd M, Johnson J, Ren X et al. Autophagy induced by conventional chemotherapy mediates tumor cell sensitivity to immunotherapy. Cancer Res 2012; 72: 5483–5493.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Kim S, Ramakrishnan R, Lavilla-Alonso S, Chinnaiyan P, Rao N, Fowler E et al. Radiation-induced autophagy potentiates immunotherapy of cancer via up-regulation of mannose 6-phosphate receptor on tumor cells in mice. Cancer Immunol Immunother 2014; 63: 1009–1021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015; 372: 320–330.

    Article  CAS  PubMed  Google Scholar 

  78. Amaravadi RK, Yu D, Lum JJ, Bui T, Christophorou MA, Evan GI et al. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest 2007; 117: 326–336.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Rebecca VW, Massaro RR, Fedorenko IV, Sondak VK, Anderson AR, Kim E et al. Inhibition of autophagy enhances the effects of the AKT inhibitor MK-2206 when combined with paclitaxel and carboplatin in BRAF wild-type melanoma. Pigment Cell Melanoma Res 2014; 27: 465–478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Cheng Y, Zhang Y, Zhang L, Ren X, Huber-Keener KJ, Liu X et al. MK-2206, a novel allosteric inhibitor of Akt, synergizes with gefitinib against malignant glioma via modulating both autophagy and apoptosis. Mol Cancer Ther 2012; 11: 154–164.

    Article  CAS  PubMed  Google Scholar 

  81. Chang Z, Shi G, Jin J, Guo H, Guo X, Luo F et al. Dual PI3K/mTOR inhibitor NVP-BEZ235-induced apoptosis of hepatocellular carcinoma cell lines is enhanced by inhibitors of autophagy. Int J Mol Med 2013; 31: 1449–1456.

    Article  CAS  PubMed  Google Scholar 

  82. Levy JM, Thompson JC, Griesinger AM, Amani V, Donson AM, Birks DK et al. Autophagy inhibition improves chemosensitivity in BRAF(V600E) brain tumors. Cancer Discov 2014; 4: 773–780.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Bray K, Mathew R, Lau A, Kamphorst JJ, Fan J, Chen J et al. Autophagy suppresses RIP kinase-dependent necrosis enabling survival to mTOR inhibition. PloS One 2012; 7: e41831.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Xie X, White EP, Mehnert JM . Coordinate autophagy and mTOR pathway inhibition enhances cell death in melanoma. PloS One 2013; 8: e55096.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Carew JS, Nawrocki ST, Kahue CN, Zhang H, Yang C, Chung L et al. Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-Abl-mediated drug resistance. Blood 2007; 110: 313–322.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Qiu L, Yao M, Gao M, Zhao Q . Doxorubicin and chloroquine coencapsulated liposomes: preparation and improved cytotoxicity on human breast cancer cells. J Liposome Res 2012; 22: 245–253.

    Article  CAS  PubMed  Google Scholar 

  87. Kraya AA, Piao S, Xu X, Zhang G, Herlyn M, Gimotty P et al. Identification of secreted proteins that reflect autophagy dynamics within tumor cells. Autophagy 2014; 11: 60–74.

    Article  PubMed Central  Google Scholar 

  88. McAfee Q, Zhang Z, Samanta A, Levi SM, Ma XH, Piao S et al. Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency. Proc Natl Acad Sci USA 2012; 109: 8253–8258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ronan B, Flamand O, Vescovi L, Dureuil C, Durand L, Fassy F et al. A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy. Nat Chem Biol 2014; 10: 1013–1019.

    Article  CAS  PubMed  Google Scholar 

  90. Dowdle WE, Nyfeler B, Nagel J, Elling RA, Liu S, Triantafellow E et al. Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo. Nat Cell Biol 2014; 16: 1069–1079.

    Article  CAS  PubMed  Google Scholar 

  91. Maes H, Kuchnio A, Peric A, Moens S, Nys K, De Bock K et al. Tumor vessel normalization by chloroquine independent of autophagy. Cancer Cell 2014; 26: 190–206.

    Article  CAS  PubMed  Google Scholar 

  92. Goodall ML, Wang T, Martin KR, Kortus MG, Kauffman AL, Trent JM et al. Development of potent autophagy inhibitors that sensitize oncogenic BRAF V600E mutant melanoma tumor cells to vemurafenib. Autophagy 2014; 10: 1120–1136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Guo JY, Xia B, White E . Autophagy-mediated tumor promotion. Cell 2013; 155: 1216–1219.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. 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 

  95. Bowman CJ, Ayer DE, Dynlacht BD . Foxk proteins repress the initiation of starvation-induced atrophy and autophagy programs. Nat Cell Biol 2014; 16: 1202–1214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. 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: 1429–1433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kenzelmann Broz D, Spano Mello S, Bieging KT, Jiang D, Dusek RL, Brady CA et al. Global genomic profiling reveals an extensive p53-regulated autophagy program contributing to key p53 responses. Genes Dev 2013; 27: 1016–1031.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Pike LR, Singleton DC, Buffa F, Abramczyk O, Phadwal K, Li JL et al. Transcriptional up-regulation of ULK1 by ATF4 contributes to cancer cell survival. Biochem J 2013; 449: 389–400.

    Article  CAS  PubMed  Google Scholar 

  99. 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: 468–471.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Jewell JL, Russell RC, Guan KL . Amino acid signalling upstream of mTOR. Nat Rev Mol Cell Biol 2013; 14: 133–139.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Eisenberg T, Schroeder S, Buttner S, Carmona-Gutierrez D, Pendl T, Andryushkova A et al. A histone point mutation that switches on autophagy. Autophagy 2014; 10: 1143–1145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Shukla S, Patric IR, Patil V, Shwetha SD, Hegde AS, Chandramouli BA et al. Methylation silencing of ULK2, an autophagy gene, is essential for astrocyte transformation and tumor growth. J Biol Chem 2014; 289: 22306–22318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Denton D, Aung-Htut MT, Lorensuhewa N, Nicolson S, Zhu W, Mills K et al. UTX coordinates steroid hormone-mediated autophagy and cell death. Nat Commun 2013; 4: 2916.

    Article  PubMed  CAS  Google Scholar 

  104. Cherra SJ 3rd, Kulich SM, Uechi G, Balasubramani M, Mountzouris J, Day BW et al. Regulation of the autophagy protein LC3 by phosphorylation. J Cell Biol 2010; 190: 533–539.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Wani WY, Boyer-Guittaut M, Dodson M, Chatham J, Darley-Usmar V, Zhang J . Regulation of autophagy by protein post-translational modification. Lab Invest 2014; 95: 14–25.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Eisenberg T, Schroeder S, Andryushkova A, Pendl T, Kuttner V, Bhukel A et al. Nucleocytosolic depletion of the energy metabolite acetyl-coenzyme a stimulates autophagy and prolongs lifespan. Cell Metab 2014; 19: 431–444.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Platta HW, Abrahamsen H, Thoresen SB, Stenmark H . Nedd4-dependent lysine-11-linked polyubiquitination of the tumour suppressor Beclin 1. Biochem J 2012; 441: 399–406.

    Article  CAS  PubMed  Google Scholar 

  108. Sarraf SA, Raman M, Guarani-Pereira V, Sowa ME, Huttlin EL, Gygi SP et al. Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization. Nature 2013; 496: 372–376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Tomar D, Singh R, Singh AK, Pandya CD, Singh R . TRIM13 regulates ER stress induced autophagy and clonogenic ability of the cells. Biochim Biophys Acta 2012; 1823: 316–326.

    Article  CAS  PubMed  Google Scholar 

  110. Kuang E, Qi J, Ronai Z . Emerging roles of E3 ubiquitin ligases in autophagy. Trends Biochem Sci 2013; 38: 453–460.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Harder LM, Bunkenborg J, Andersen JS . Inducing autophagy: a comparative phosphoproteomic study of the cellular response to ammonia and rapamycin. Autophagy 2014; 10: 339–355.

    Article  CAS  PubMed  Google Scholar 

  112. Ye J, Kumanova M, Hart LS, Sloane K, Zhang H, De Panis DN et al. The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation. Embo J 2010; 29: 2082–2096.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Zoncu R, Bar-Peled L, Efeyan A, Wang S, Sancak Y, Sabatini DM . mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase. Science 2011; 334: 678–683.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Marino G, Pietrocola F, Eisenberg T, Kong Y, Malik SA, Andryushkova A et al. Regulation of autophagy by cytosolic acetyl-coenzyme A. Mol Cell 2014; 53: 710–725.

    Article  CAS  PubMed  Google Scholar 

  115. Duran RV, Oppliger W, Robitaille AM, Heiserich L, Skendaj R, Gottlieb E et al. Glutaminolysis activates Rag-mTORC1 signaling. Mol Cell 2012; 47: 349–358.

    Article  CAS  PubMed  Google Scholar 

  116. Mathew R, Khor S, Hackett SR, Rabinowitz JD, Perlman DH, White E . Functional role of autophagy-mediated proteome remodeling in cell survival signaling and innate immunity. Mol Cell 2014; 55: 916–930.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Horikawa I, Fujita K, Jenkins LM, Hiyoshi Y, Mondal AM, Vojtesek B et al. Autophagic degradation of the inhibitory p53 isoform Delta133p53alpha as a regulatory mechanism for p53-mediated senescence. Nat Commun 2014; 5: 4706.

    Article  CAS  PubMed  Google Scholar 

  118. Lan YY, Londono D, Bouley R, Rooney MS, Hacohen N . Dnase2a deficiency uncovers lysosomal clearance of damaged nuclear DNA via autophagy. Cell Rep 2014; 9: 180–192.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Thorburn J, Andrysik Z, Staskiewicz L, Gump J, Maycotte P, Oberst A et al. Autophagy controls the kinetics and extent of mitochondrial apoptosis by regulating PUMA levels. Cell Rep 2014; 7: 45–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. 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: 20–30.

    Article  CAS  PubMed  Google Scholar 

  121. Krysko DV, Garg AD, Kaczmarek A, Krysko O, Agostinis P, Vandenabeele P . Immunogenic cell death and DAMPs in cancer therapy. Nat Rev Cancer 2012; 12: 860–875.

    Article  CAS  PubMed  Google Scholar 

  122. Martins I, Wang Y, Michaud M, Ma Y, Sukkurwala AQ, Shen S et al. Molecular mechanisms of ATP secretion during immunogenic cell death. Cell Death Differ 2014; 21: 79–91.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by R01 CA169134 (RKA) from the National Institutes of Health.

Author information

Authors and Affiliations

  1. The Department of Medicine and Abramson Cancer Center; University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    V W Rebecca & R K Amaravadi

Authors
  1. V W Rebecca
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R K Amaravadi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R K Amaravadi.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rebecca, V., Amaravadi, R. Emerging strategies to effectively target autophagy in cancer. Oncogene 35, 1–11 (2016). https://doi.org/10.1038/onc.2015.99

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2015.99

This article is cited by

Search

Advanced search

Quick links