Autophagy as a Therapeutic Target in Cancer

Part of the Current Cancer Research book series (CUCR)


Autophagy is the process by which cellular material is delivered to the lysosome for degradation and recycling. Macroautophagy involves delivery of macromolecules and organelles to double membrane vesicles called autophagosomes that fuse with lysosomes leading to degradation of the contents of the autophagosomes. Chaperone-mediated autophagy involves direct recognition of specific proteins by chaperone complexes that then directly deliver the protein target to the lysosome. Microautophagy involves direct lysosomal capture of cytoplasmic material. Of these three types, macroautophagy is by far the most studied and is known to have multiple roles in cancer development, progression and response to therapy. This has led to autophagy being widely viewed as a potential therapeutic target in cancer. Important questions that must be answered include: Which tumors should or should not be treated by direct autophagy inhibition? And, what is the best way to target autophagy for cancer therapy? In this overview we summarize the background and some current ideas about the answers to such questions.


Autophagy Apoptosis Cancer therapy ATG7 BRAF KRAS 


  1. Amaravadi, R. K., Yu, D., Lum, J. J., Bui, T., Christophorou, M. A., Evan, G. I., et al. (2007). Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. Journal of Clinical Investigation, 117, 326–336.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Arias, E., & Cuervo, A. M. (2011). Chaperone-mediated autophagy in protein quality control. Current Opinion in Cell Biology, 23, 184–189.CrossRefPubMedGoogle Scholar
  3. Baginska, J., Viry, E., Berchem, G., Poli, A., Noman, M. Z., Van Moer, K., et al. (2013). Granzyme B degradation by autophagy decreases tumor cell susceptibility to natural killer-mediated lysis under hypoxia. Proceedings of the National Academy of Sciences of the United States of America, 110, 17450–17455.Google Scholar
  4. Bago, R., Malik, N., Munson, M. J., Prescott, A. R., Davies, P., Sommer, E., et al. (2014). Characterization of VPS34-IN1, a selective inhibitor of Vps34, reveals that the phosphatidylinositol 3-phosphate-binding SGK3 protein kinase is a downstream target of class III phosphoinositide 3-kinase. The Biochemical Journal, 463, 413–427.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Barnard, R. A., Wittenburg, L. A., Amaravadi, R. K., Gustafson, D. L., Thorburn, A., & Thamm, D. H. (2014). Phase I clinical trial and pharmacodynamic evaluation of combination hydroxychloroquine and doxorubicin treatment in pet dogs treated for spontaneously occurring lymphoma. Autophagy, 10, 1415–1425.CrossRefPubMedPubMedCentralGoogle Scholar
  6. Bursch, W., Ellinger, A., Kienzl, H., Torok, L., Pandey, S., Sikorska, M., et al. (1996). Active cell death induced by the anti-estrogens tamoxifen and ICI 164 384 in human mammary carcinoma cells (MCF-7) in culture: The role of autophagy. Carcinogenesis, 17, 1595–1607.CrossRefPubMedGoogle Scholar
  7. Chourasia, A. H., Tracy, K., Frankenberger, C., Boland, M. L., Sharifi, M. N., Drake, L. E., et al. (2015). Mitophagy defects arising from BNip3 loss promote mammary tumor progression to metastasis. EMBO Reports, 16, 1145–1163.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Dowdle, W. E., Nyfeler, B., Nagel, J., Elling, R. A., Liu, S., Triantafellow, E., et al. (2014). Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo. Nature Cell Biology, 16(11), 1069–1079.CrossRefPubMedGoogle Scholar
  9. Egan, D. F., Chun, M. G. H., Vamos, M., Zou, H., Rong, J., Miller, C. J., et al. (2015). Small Molecule Inhibition of the autophagy kinase ULK1 and Identification of ULK1 substrates. Molecular Cell, 59, 285–297.CrossRefPubMedPubMedCentralGoogle Scholar
  10. Eng, C. H., Wang, Z., Tkach, D., Toral-Barza, L., Ugwonali, S., Liu, S., et al. (2016). Macroautophagy is dispensable for growth of KRAS mutant tumors and chloroquine efficacy. Proceedings of the National Academy of Sciences of the United States of America, 113, 182–187.Google Scholar
  11. Fitzwalter, B. E., & Thorburn, A. (2015). Recent insights into cell death and autophagy. The FEBS Journal, 282, 4279–4288.CrossRefPubMedGoogle Scholar
  12. Galluzzi, L., Pietrocola, F., Pedro Bravo-San, J. M., Amaravadi, R. K., Baehrecke, E. H., Cecconi, F., et al. (2015). Autophagy in malignant transformation and cancer progression. The EMBO Journal, 34(7), 856–880.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Goodall, M. L., Wang, T., Martin, K. R., Kortus, M. G., Kauffman, A. L., Trent, J. M., et al. (2014). Development of potent autophagy inhibitors that sensitize oncogenic BRAF V600E mutant melanoma tumor cells to vemurafenib. Autophagy, 10, 1120–1136.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Gump, J. M., Staskiewicz, L., Morgan, M. J., Bamberg, A., Riches, D. W. H., & Thorburn, A. (2014). Autophagy variation within a cell population determines cell fate through selective degradation of Fap-1. Nature Cell Biology, 16, 47–54.CrossRefPubMedGoogle Scholar
  15. Guo, J. Y., Chen, H.-Y., Mathew, R., Fan, J., Strohecker, A. M., Karsli-Uzunbas, G., et al. (2011). Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes and Development, 25, 460–470.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Guo, J. Y., Karsli-Uzunbas, G., Mathew, R., Aisner, S. C., Kamphorst, J. J., Strohecker, A. M., et al. (2013a). Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis. Genes and Development, 27, 1447–1461.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Guo, J. Y., Xia, B., & White, E. (2013b). Autophagy-mediated tumor promotion. Cell, 155, 1216–1219.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Hippert, M. M., O’Toole, P. S., & Thorburn, A. (2006). Autophagy in cancer: Good, bad, or both? Cancer Research, 66, 9349–9351.CrossRefPubMedGoogle Scholar
  19. Holohan, C., Van Schaeybroeck, S., Longley, D. B., & Johnston, P. G. (2013). Cancer drug resistance: An evolving paradigm. Nature Reviews Cancer, 13, 714–726.CrossRefPubMedGoogle Scholar
  20. Huo, Y., Cai, H., Teplova, I., Bowman-Colin, C., Chen, G., Price, S., et al. (2013). Autophagy opposes p53-mediated tumor barrier to facilitate tumorigenesis in a model of PALB2-associated hereditary breast cancer. Cancer Discovery, 3, 894–907.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Joshi, S., Tolkunov, D., Aviv, H., Hakimi, A. A., Yao, M., Hsieh, J. J., et al. (2015). The genomic landscape of renal oncocytoma identifies a metabolic barrier to tumorigenesis. Cell Reports, 13, 1895–1908.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Karsli-Uzunbas, G., Guo, J. Y., Price, S., Teng, X., Laddha, S. V., Khor, S., et al. (2014). Autophagy is required for glucose homeostasis and lung tumor maintenance. Cancer Discovery, 4, 914–927.CrossRefPubMedPubMedCentralGoogle Scholar
  23. Kaur, J., & Debnath, J. (2015). Autophagy at the crossroads of catabolism and anabolism. Nature Reviews Molecular Cell Biology, 16, 461–472.CrossRefPubMedGoogle Scholar
  24. Kaushik, S., Bandyopadhyay, U., Sridhar, S., Kiffin, R., Martinez-Vicente, M., Kon, M., et al. (2011). Chaperone-mediated autophagy at a glance. Journal of Cell Science, 124, 495–499.CrossRefPubMedPubMedCentralGoogle Scholar
  25. Kimmey, J. M., Huynh, J. P., Weiss, L. A., Park, S., Kambal, A., Debnath, J., et al. (2015). Unique role for ATG5 in neutrophil-mediated immunopathology during M. tuberculosis infection. Nature, 528, 565–569.CrossRefPubMedPubMedCentralGoogle Scholar
  26. Kroemer, G. (2015). Autophagy: A druggable process that is deregulated in aging and human disease. Journal of Clinical Investigation, 125, 1–4.CrossRefPubMedPubMedCentralGoogle Scholar
  27. Laddha, S. V., Ganesan, S., Chan, C. S., & White, E. (2014). Mutational landscape of the essential autophagy gene BECN1 in human cancers. Molecular Cancer Research, 12, 485–490.CrossRefPubMedPubMedCentralGoogle Scholar
  28. Lee, I. H., Kawai, Y., Fergusson, M. M., Rovira, I. I., Bishop, A. J. R., Motoyama, N., et al. (2012). Atg7 modulates p53 activity to regulate cell cycle and survival during metabolic stress. Science, 336, 225–228.CrossRefPubMedPubMedCentralGoogle Scholar
  29. Levy, J. M. M., Thompson, J. C., Griesinger, A. M., Amani, V., Donson, A. M., Birks, D. K., et al. (2014). Autophagy inhibition improves chemosensitivity in BRAFV600E brain tumors. Cancer Discovery, 4, 773–780.CrossRefPubMedPubMedCentralGoogle Scholar
  30. Levy, J. M., & Thorburn, A. (2011). Targeting autophagy during cancer therapy to improve clinical outcomes. Pharmacology and Therapeutics, 131, 130–141.CrossRefPubMedPubMedCentralGoogle Scholar
  31. Levy, J. M., & Thorburn, A. (2012). Modulation of pediatric brain tumor autophagy and chemosensitivity. Journal of Neuro-Oncology, 106, 281–290.CrossRefPubMedGoogle Scholar
  32. Li, Y., Hahn, T., Garrison, K., Cui, Z. H., Thorburn, A., Thorburn, J., et al. (2012). The vitamin E analogue alpha-TEA stimulates tumor autophagy and enhances antigen cross-presentation. Cancer Research, 72, 3535–3545.CrossRefPubMedPubMedCentralGoogle Scholar
  33. Liang, X., de Vera, M. E., Buchser, W. J., Romo De Vivar Chavez, A., Loughran, P., Beer Stolz, D., et al. (2012). Inhibiting systemic autophagy during interleukin 2 immunotherapy promotes long-term tumor regression. Cancer Research, 72, 2791–2801.CrossRefPubMedPubMedCentralGoogle Scholar
  34. Liang, C., Feng, P., Ku, B., Dotan, I., Canaani, D., Oh, B. H., et al. (2006). Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG. Nature Cell Biology, 8, 688–698.CrossRefPubMedGoogle Scholar
  35. Lock, R., Kenific, C. M., Leidal, A. M., Salas, E., & Debnath, J. (2014). Autophagy-dependent production of secreted factors facilitates oncogenic RAS-driven invasion. Cancer Discovery, 4, 466–479.CrossRefPubMedPubMedCentralGoogle Scholar
  36. Lock, R., Roy, S., Kenific, C. M., Su, J. S., Salas, E., Ronen, S. M., et al. (2011). Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation. Molecular Biology of the Cell, 22, 165–178.CrossRefPubMedPubMedCentralGoogle Scholar
  37. Ma, X.-H., Piao, S.-F., Dey, S., McAfee, Q., Karakousis, G., Villanueva, J., et al. (2014). Targeting ER stress-induced autophagy overcomes BRAF inhibitor resistance in melanoma. Journal of Clinical Investigation, 124, 1406–1417.CrossRefPubMedPubMedCentralGoogle Scholar
  38. Maejima, I., Takahashi, A., Omori, H., Kimura, T., Takabatake, Y., Saitoh, T., et al. (2013). Autophagy sequesters damaged lysosomes to control lysosomal biogenesis and kidney injury. The EMBO Journal, 32, 2336–2347.CrossRefPubMedPubMedCentralGoogle Scholar
  39. Mancias, J. D., & Kimmelman, A. C. (2011). Targeting autophagy addiction in cancer. Oncotarget, 2, 1302–1306.CrossRefPubMedPubMedCentralGoogle Scholar
  40. Mancias, J. D., Wang, X., Gygi, S. P., Harper, J. W., & Kimmelman, A. C. (2014). Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature, 509, 105–109.CrossRefPubMedPubMedCentralGoogle Scholar
  41. Marino, G., Salvador-Montoliu, N., Fueyo, A., Knecht, E., Mizushima, N., & Lopez-Otin, C. (2007). Tissue-specific autophagy alterations and increased tumorigenesis in mice deficient in Atg4C/autophagin-3. Journal of Biological Chemistry, 282, 18573–18583.CrossRefPubMedGoogle Scholar
  42. Martinez-Lopez, N., Athonvarangkul, D., Mishall, P., Sahu, S., & Singh, R. (2013). Autophagy proteins regulate ERK phosphorylation. Nature Communications, 4, 2799.CrossRefPubMedPubMedCentralGoogle Scholar
  43. Maskey, D., Yousefi, S., Schmid, I., Zlobec, I., Perren, A., Friis, R., et al. (2013). ATG5 is induced by DNA-damaging agents and promotes mitotic catastrophe independent of autophagy. Nature Communications, 4, 2130.CrossRefPubMedPubMedCentralGoogle Scholar
  44. Mathew, R., Khor, S., Hackett, S. R., Rabinowitz, J. D., Perlman, D. H., & White, E. (2014). Functional role of autophagy-mediated proteome remodeling in cell survival signaling and innate immunity. Molecular Cell, 55, 916–930.CrossRefPubMedPubMedCentralGoogle Scholar
  45. Maycotte, P., Aryal, S., Cummings, C. T., Thorburn, J., Morgan, M. J., & Thorburn, A. (2012). Chloroquine sensitizes breast cancer cells to chemotherapy independent of autophagy. Autophagy, 8, 200–212.CrossRefPubMedPubMedCentralGoogle Scholar
  46. Maycotte, P., Gearheart, C. M., Barnard, R., Aryal, S., Mulcahy Levy, J. M., Fosmire, S. P., et al. (2014). STAT3-mediated autophagy dependence identifies subtypes of breast cancer where autophagy inhibition can be efficacious. Cancer Research, 74, 2579–2590.CrossRefPubMedPubMedCentralGoogle Scholar
  47. Maycotte, P., Jones, K. L., Goodall, M. L., Thorburn, J., & Thorburn, A. (2015). Autophagy supports breast cancer stem cell maintenance by regulating IL6 secretion. Molecular Cancer Research, 13(4), 651–658.CrossRefPubMedPubMedCentralGoogle Scholar
  48. Maycotte, P., & Thorburn, A. (2011). Autophagy and cancer therapy. Cancer Biology and Therapy, 11, 127–137.CrossRefPubMedPubMedCentralGoogle Scholar
  49. Mcafee, Q., Zhang, Z., Samanta, A., Levi, S. M., Ma, X.-H., Piao, S., et al. (2012). Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency. Proceedings of the National Academy of Science of the United States of America, 109(21), 8253–8258.Google Scholar
  50. Michaud, M., Martins, I., Sukkurwala, A. Q., Adjemian, S., Ma, Y., Pellegatti, P., et al. (2011). Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science, 334, 1573–1577.CrossRefPubMedGoogle Scholar
  51. Mizushima, N., Yoshimori, T., & Ohsumi, Y. (2011). The role of Atg proteins in autophagosome formation. Annual Review of Cell and Developmental Biology, 27, 107–132.CrossRefPubMedGoogle Scholar
  52. Mochida, K., Oikawa, Y., Kimura, Y., Kirisako, H., Hirano, H., Ohsumi, Y., et al. (2015). Receptor-mediated selective autophagy degrades the endoplasmic reticulum and the nucleus. Nature, 522, 359–362.CrossRefPubMedGoogle Scholar
  53. Morgan, M. J., Gamez, G., Menke, C., Hernandez, A., Thorburn, J., Gidan, F., et al. (2014). Regulation of autophagy and chloroquine sensitivity by oncogenic RAS in vitro is context-dependent. Autophagy, 10, 1814–1826.CrossRefPubMedPubMedCentralGoogle Scholar
  54. Perera, R. M., Stoykova, S., Nicolay, B. N., Ross, K. N., Fitamant, J., Boukhali, M., et al. (2015). Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism. Nature, 524, 361–365.CrossRefPubMedGoogle Scholar
  55. Pérez, E., Das, G., Bergmann, A., & Baehrecke, E. H. (2015). Autophagy regulates tissue overgrowth in a context-dependent manner. Oncogene, 34, 3369–3376.CrossRefPubMedGoogle Scholar
  56. Petherick, K. J., Conway, O. J. L., Mpamhanga, C., Osborne, S. A., Kamal, A., Saxty, B., et al. (2015). Pharmacological inhibition of ULK1 kinase blocks mammalian target of rapamycin (mTOR)-dependent autophagy. The Journal of Biological Chemistry, 290, 11376–11383.CrossRefPubMedPubMedCentralGoogle Scholar
  57. Qu, X., Yu, J., Bhagat, G., Furuya, N., Hibshoosh, H., Troxel, A., et al. (2003). Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. Journal of Clinical Investigation, 112, 1809–1820.CrossRefPubMedPubMedCentralGoogle Scholar
  58. Radoshevich, L., Murrow, L., Chen, N., Fernandez, E., Roy, S., Fung, C., et al. (2010). ATG12 conjugation to ATG3 regulates mitochondrial homeostasis and cell death. Cell, 142, 590–600.CrossRefPubMedPubMedCentralGoogle Scholar
  59. Randow, F., & Youle, R. J. (2014). Self and nonself: How autophagy targets mitochondria and bacteria. Cell Host & Microbe, 15, 403–411.CrossRefGoogle Scholar
  60. Rangwala, R., Chang, Y. C., Hu, J., Algazy, K., Evans, T., Fecher, L., et al. (2014a). Combined MTOR and autophagy inhibition: Phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma. Autophagy, 10, 1391–1402.CrossRefPubMedPubMedCentralGoogle Scholar
  61. Rangwala, R., Leone, R., Chang, Y. C., Fecher, L., Schuchter, L., Kramer, A., et al. (2014b). Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma. Autophagy, 10, 1369–1379.CrossRefPubMedPubMedCentralGoogle Scholar
  62. Rao, S., Tortola, L., Perlot, T., Wirnsberger, G., Novatchkova, M., Nitsch, R., et al. (2014). A dual role for autophagy in a murine model of lung cancer. Nature Communications, 5, 3056.CrossRefPubMedGoogle Scholar
  63. Rebecca, V. W., & Amaravadi, R. K. (2015). Emerging strategies to effectively target autophagy in cancer. Oncogene, 35(11), 1–11.PubMedPubMedCentralGoogle Scholar
  64. Ronan, B., Flamand, O., Vescovi, L., Dureuil, C., Durand, L., Fassy, F., et al. (2014). A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy. Nature Chemical Biology, 10, 1013–1019.CrossRefPubMedGoogle Scholar
  65. Rosenfeld, M. R., Ye, X., Supko, J. G., Desideri, S., Grossman, S. A., Brem, S., et al. (2014). 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, 10, 1359–1368.CrossRefPubMedPubMedCentralGoogle Scholar
  66. Rosenfeldt, M. T., O’Prey, J., Morton, J. P., Nixon, C., MacKay, G., Mrowinska, A., et al. (2013). p53 status determines the role of autophagy in pancreatic tumour development. Nature, 504, 296–300.CrossRefPubMedGoogle Scholar
  67. Rubinstein, A. D., Eisenstein, M., Ber, Y., Bialik, S., & Kimchi, A. (2011). The autophagy protein Atg12 associates with antiapoptotic Bcl-2 family members to promote mitochondrial apoptosis. Molecular Cell, 44, 698–709.CrossRefPubMedGoogle Scholar
  68. Rubinsztein, D. C., Codogno, P., & Levine, B. (2012). Autophagy modulation as a potential therapeutic target for diverse diseases. Nature Reviews Drug Discovery, 11, 709–730.CrossRefPubMedPubMedCentralGoogle Scholar
  69. Sahu, R., Kaushik, S., Clement, C. C., Cannizzo, E. S., Scharf, B., Follenzi, A., et al. (2011). Microautophagy of cytosolic proteins by late endosomes. Developmental Cell, 20, 131–139.CrossRefPubMedPubMedCentralGoogle Scholar
  70. Shen, S., Kepp, O., Michaud, M., Martins, I., Minoux, H., Métivier, D., et al. (2011). Association and dissociation of autophagy, apoptosis and necrosis by systematic chemical study. Oncogene, 30(45), 4544–4556.CrossRefPubMedGoogle Scholar
  71. Shimizu, S., Kanaseki, T., Mizushima, N., Mizuta, T., Arakawa-Kobayashi, S., Thompson, C. B., et al. (2004). Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nature Cell Biology, 6, 1221–1228.CrossRefPubMedGoogle Scholar
  72. Singh, R., Kaushik, S., Wang, Y., Xiang, Y., Novak, I., Komatsu, M., et al. (2009). Autophagy regulates lipid metabolism. Nature, 458, 1131–1135.CrossRefPubMedPubMedCentralGoogle Scholar
  73. Strohecker, A. M., Guo, J. Y., Karsli-Uzunbas, G., Price, S. M., Chen, G. J., Mathew, R., et al. (2013). Autophagy sustains mitochondrial glutamine metabolism and growth of BRAFV600E-driven lung tumors. Cancer Discovery, 3, 1272–1285.CrossRefPubMedGoogle Scholar
  74. Subramani, S., & Malhotra, V. (2013). Non-autophagic roles of autophagy-related proteins. EMBO Reports, 14, 143–151.CrossRefPubMedPubMedCentralGoogle Scholar
  75. Takahashi, Y., Coppola, D., Matsushita, N., Cualing, H. D., Sun, M., Sato, Y., et al. (2007). Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nature Cell Biology, 9, 1142–1151.CrossRefPubMedPubMedCentralGoogle Scholar
  76. Takamura, A., Komatsu, M., Hara, T., Sakamoto, A., Kishi, C., Waguri, S., et al. (2011). Autophagy-deficient mice develop multiple liver tumors. Genes and Development, 25, 795–800.CrossRefPubMedPubMedCentralGoogle Scholar
  77. Tang, H., Sebti, S., Titone, R., Zhou, Y., Isidoro, C., Ross, T. S., et al. (2015). Decreased BECN1 mRNA expression in human breast cancer is associated with estrogen receptor-negative subtypes and poor prognosis. EBioMedicine, 2, 255–263.CrossRefPubMedPubMedCentralGoogle Scholar
  78. Thorburn, A. (2008). Studying autophagy’s relationship to cell death. Autophagy, 4, 391–394.CrossRefPubMedPubMedCentralGoogle Scholar
  79. Thorburn, A. (2011). I think autophagy controls the death of my cells: What do I do to get my paper published? Autophagy, 7, 455–456.CrossRefPubMedGoogle Scholar
  80. Thorburn, A. (2014). Autophagy and its effects: Making sense of double-edged swords. PLoS Biology, 12, e1001967.CrossRefPubMedPubMedCentralGoogle Scholar
  81. Thorburn, J., Horita, H., Redzic, J., Hansen, K., Frankel, A. E., & Thorburn, A. (2009). Autophagy regulates selective HMGB1 release in tumor cells that are destined to die. Cell Death and Differentiation, 16, 175–183.CrossRefPubMedGoogle Scholar
  82. Thorburn, A., & Morgan, M. J. (2015). Targeting autophagy in BRAF-mutant tumors. Cancer Discovery, 5, 353–354.CrossRefPubMedPubMedCentralGoogle Scholar
  83. Thorburn, A., Thamm, D. H., & Gustafson, D. L. (2014). Autophagy and cancer therapy. Molecular Pharmacology, 85, 830–838.CrossRefPubMedPubMedCentralGoogle Scholar
  84. Thoresen, S. B., Pedersen, N. M., Liestøl, K., & Stenmark, H. (2010). A phosphatidylinositol 3-kinase class III sub-complex containing VPS15, VPS34, Beclin 1, UVRAG and BIF-1 regulates cytokinesis and degradative endocytic traffic. Experimental Cell Research, 316, 3368–3378.CrossRefPubMedGoogle Scholar
  85. Veldhoen, R. A., Banman, S. L., Hemmerling, D. R., Odsen, R., Simmen, T., Simmonds, A. J., et al. (2013). The chemotherapeutic agent paclitaxel inhibits autophagy through two distinct mechanisms that regulate apoptosis. Oncogene, 32, 736–746.CrossRefPubMedGoogle Scholar
  86. Vogl, D. T., Stadtmauer, E. A., Tan, K.-S., Heitjan, D. F., Davis, L. E., Pontiggia, L., et al. (2014). Combined autophagy and proteasome inhibition: A phase 1 trial of hydroxychloroquine and bortezomib in patients with relapsed/refractory myeloma. Autophagy, 10, 1380–1390.CrossRefPubMedPubMedCentralGoogle Scholar
  87. Wei, H., Wang, C., Croce, C. M., & Guan, J.-L. (2014). p62/SQSTM1 synergizes with autophagy for tumor growth in vivo. Genes and Development, 28, 1204–1216.CrossRefPubMedPubMedCentralGoogle Scholar
  88. Wei, H., Wei, S., Gan, B., Peng, X., Zou, W., & Guan, J.-L. (2011). Suppression of autophagy by FIP200 deletion inhibits mammary tumorigenesis. Genes and Development, 25, 1510–1527.CrossRefPubMedPubMedCentralGoogle Scholar
  89. Wei, Y., Zou, Z., Becker, N., Anderson, M., Sumpter, R., Xiao, G., et al. (2013). EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance. Cell, 154, 1269–1284.CrossRefPubMedPubMedCentralGoogle Scholar
  90. White, E. (2012). Deconvoluting the context-dependent role for autophagy in cancer. Nature Reviews Cancer, 12, 401–410.CrossRefPubMedPubMedCentralGoogle Scholar
  91. Wolpin, B. M., Rubinson, D. A., Wang, X., Chan, J. A., Cleary, J. M., Enzinger, P. C., et al. (2014). Phase II and pharmacodynamic study of autophagy inhibition using hydroxychloroquine in patients with metastatic pancreatic adenocarcinoma. The Oncologist, 19, 637–638.CrossRefPubMedPubMedCentralGoogle Scholar
  92. Xie, X., Koh, J. Y., Price, S., White, E., & Mehnert, J. M. (2015). Atg7 overcomes senescence and promotes growth of BrafV600E-driven melanoma. Cancer Discovery, 5, 410–423.CrossRefPubMedPubMedCentralGoogle Scholar
  93. Xie, X., White, E. P., & Mehnert, J. M. (2013). Coordinate autophagy and mTOR pathway inhibition enhances cell death in melanoma. PLoS One, 8, e55096.CrossRefPubMedPubMedCentralGoogle Scholar
  94. Yang, A., Rajeshkumar, N. V., Wang, X., Yabuuchi, S., Alexander, B. M., Chu, G. C., et al. (2014). Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations. Cancer Discovery, 4, 905–913.CrossRefPubMedPubMedCentralGoogle Scholar
  95. Yang, S., Wang, X., Contino, G., Liesa, M., Sahin, E., Ying, H., et al. (2011). Pancreatic cancers require autophagy for tumor growth. Genes and Development, 25, 717–729.CrossRefPubMedPubMedCentralGoogle Scholar
  96. Yue, Z., Jin, S., Yang, C., Levine, A. J., & Heintz, N. (2003). Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proceedings of the National Academy of Sciences of the United States of America, 100, 15077–15082.CrossRefPubMedPubMedCentralGoogle Scholar
  97. Zhao, Z., Oh, S., Li, D., Ni, D., Pirooz, S. D., Lee, J.-H., et al. (2012). A dual role for UVRAG in maintaining chromosomal stability independent of autophagy. Developmental Cell, 22(5), 1001–1016.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of PharmacologyUniversity of Colorado School of MedicineAuroraUSA

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