Autophagy as a target for anticancer therapy

Nature Reviews Clinical Oncology

Volumn 8, Issue 9, 2011, Pages 528-539

  Janku, Filip ^a   McConkey, David J ^a   Hong, David S ^a   Kurzrock, Razelle ^a  

^a UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; ARSENIC TRIOXIDE; BORTEZOMIB; BUTYRIC ACID; CHLOROQUINE; DACINOSTAT; DASATINIB; EPOXOMICIN; EVEROLIMUS; HYDROXYCHLOROQUINE; IMATINIB; LONAFARNIB; MAMMALIAN TARGET OF RAPAMYCIN; MEPACRINE; PANITUMUMAB; PANOBINOSTAT; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; RAPAMYCIN; RESVERATROL; RITUXIMAB; SALINOSPORAMIDE A; SEOCALCITOL; SORAFENIB; TAMOXIFEN; TEMSIROLIMUS; TOREMIFENE; UNINDEXED DRUG; VELIPARIB; VORINOSTAT;

ANTINEOPLASTIC ACTIVITY; APOPTOSIS; AUTOPHAGY; BREAST CANCER; CANCER CELL; CANCER GROWTH; CANCER INHIBITION; CHRONIC MYELOID LEUKEMIA; COLORECTAL CANCER; DRUG CYTOTOXICITY; GASTROINTESTINAL STROMAL TUMOR; GLIOBLASTOMA; HUMAN; KIDNEY CANCER; LIVER CELL CARCINOMA; LUNG NON SMALL CELL CANCER; METABOLIC STRESS; MULTIPLE MYELOMA; NONHUMAN; PRIORITY JOURNAL; PROMYELOCYTIC LEUKEMIA; PROSTATE CANCER; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; ANTINEOPLASTIC AGENTS; AUTOPHAGY; HUMANS; NEOPLASMS; SIGNAL TRANSDUCTION;

EID: 80052227050     PISSN: 17594774     EISSN: 17594782     Source Type: Journal    
DOI: 10.1038/nrclinonc.2011.71     Document Type: Review

References (154)

1. Mizushima, N. Autophagy: Process and function. Genes Dev. 21, 2861-2873 (2007). (Pubitemid 350133435)
2. Levine, B. & Klionsky, D. J. Development by self-digestion: Molecular mechanisms and biological functions of autophagy. Dev. Cell 6, 463-477 (2004). (Pubitemid 38456176)
3. Uttenweiler, A. & Mayer, A. Microautophagy in the yeast Saccharomyces cerevisiae. Methods Mol. Biol. 445, 245-259 (2008).
4. Arias, E. & Cuervo, A. M. Chaperone-mediated autophagy in protein quality control. Curr. Opin. Cell Biol. 23, 184-189 (2011).
5. Mizushima, N., Levine, B., Cuervo, A. M. & Klionsky, D. J. Autophagy fights disease through cellular self-digestion. Nature 451, 1069-1075 (2008). (Pubitemid 351317450)
6. Levine, B. Eating oneself and uninvited guests: Autophagy-related pathways in cellular defense. Cell 120, 159-162 (2005). (Pubitemid 40174758)
7. Yang, Z. & Klionsky, D. J. Eaten alive: A history of macroautophagy. Nat. Cell Biol. 12, 814-822 (2010).
8. Korolchuk, V. I., Mansilla, A., Menzies, F. M. & Rubinsztein, D. C. Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates. Mol. Cell 33, 517-527 (2009).
9. Degenhardt, K. et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 10, 51-64 (2006).
10. Apel, A., Herr, I., Schwarz, H., Rodemann, H. P. & Mayer, A. Blocked autophagy sensitizes resistant carcinoma cells to radiation therapy. Cancer Res. 68, 1485-1494 (2008). (Pubitemid 351346857)
11. Katayama, M., Kawaguchi, T., Berger, M. S. & Pieper, R. O. DNA damaging agent-induced autophagy produces a cytoprotective adenosine triphosphate surge in malignant glioma cells. Cell Death Differ. 14, 548-558 (2007).
12. Qadir, M. A. et al. Macroautophagy inhibition sensitizes tamoxifen-resistant breast cancer cells and enhances mitochondrial depolarization. Breast Cancer Res. Treat. 112, 389-403 (2008).
13. 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 4, e6251 (2009).
14. Carew, J. S. et al. Autophagy inhibition enhances vorinostat-induced apoptosis via ubiquitinated protein accumulation. J. Cell. Mol. Med. 14, 2448-2459 (2010).
15. Baehrecke, E. H. Autophagy: Dual roles in life and death? Nat. Rev. Mol. Cell Biol. 6, 505-510 (2005). (Pubitemid 40780562)
16. Kim, K. W. et al. Autophagy upregulation by inhibitors of caspase-3 and mTOR enhances radiotherapy in a mouse model of lung cancer. Autophagy 4, 659-668 (2008).
17. Kim, K. W., Moretti, L., Mitchell, L. R., Jung, D. K. & Lu, B. Combined Bcl-2/mammalian target of rapamycin inhibition leads to enhanced radiosensitization via induction of apoptosis and autophagy in non-small cell lung tumor xenograft model. Clin. Cancer Res. 15, 6096-6105 (2009).
18. Tormo, D. et al. Targeted activation of innate immunity for therapeutic induction of autophagy and apoptosis in melanoma cells. Cancer Cell 16, 103-114 (2009).
19. Weihua, Z. et al. Survival of cancer cells is maintained by EGFR independent of its kinase activity. Cancer Cell 13, 385-393 (2008). (Pubitemid 351609444)
20. Levine, B. & Yuan, J. Autophagy in cell death: An innocent convict? J. Clin. Invest. 115, 2679-2688 (2005). (Pubitemid 41434392)
21. Wullschleger, S., Loewith, R. & Hall, M. N. TOR signaling in growth and metabolism. Cell 127, 5-19 (2006).
22. Kamada, Y. et al. Tor-mediated induction of autophagy via an Apg1 protein kinase complex. J. Cell Biol. 150, 1507-1513 (2000).
23. Chang, Y. Y. & Neufeld, T. P. An Atg1/Atg13 complex with multiple roles in TOR-mediated autophagy regulation. Mol. Biol. Cell 20, 2004-2014 (2009).
24. Yang, Z. & Klionsky, D. J. Mammalian autophagy: Core molecular machinery and signaling regulation. Curr. Opin. Cell Biol. 22, 124-131 (2010).
25. He, C. K. & Klionsky, D. J. Regulation mechanisms and signaling pathways of autophagy. Annu. Rev. Genet. 43, 67-93 (2009).
26. Rodriguez-Viciana, P. et al. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370, 527-532 (1994). (Pubitemid 24264918)
27. Manning, B. D. et al. Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2. Genes Dev. 19, 1773-1778 (2005). (Pubitemid 41126916)
28. Sun, S. Y. et al. Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res. 65, 7052-7058 (2005).
29. Nicklin, P. et al. Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136, 521-534 (2009).
30. Shinojima, N., Yokoyama, T., Kondo, Y. & Kondo, S. Roles of the Akt/mTOR/p70S6K and ERK1/2 signaling pathways in curcumin-induced autophagy. Autophagy 3, 635-637 (2007). (Pubitemid 350060068)
31. Wong, C. H. et al. Simultaneous induction of non-canonical autophagy and apoptosis in cancer cells by ROS-dependent ERK and JNK activation. PLoS One 5, e9996 (2010).
32. Xie, Z. & Klionsky, D. J. Autophagosome formation: Core machinery and adaptations. Nat. Cell Biol. 9, 1102-1109 (2007). (Pubitemid 47500484)
33. Hayashi-Nishino, M. et al. A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Nat. Cell Biol. 11, 1433-1437 (2009).
34. Nishida, Y. et al. Discovery of Atg5/Atg7-independent alternative macroautophagy. Nature 461, 654-658 (2009).
35. Hailey, D. W. et al. Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell 141, 656-667 (2010).
36. Ravikumar, B., Moreau, K., Jahreiss, L., Puri, C. & Rubinsztein, D. C. Plasma membrane contributes to the formation of pre-Autophagosomal structures. Nat. Cell Biol. 12, 747-757 (2010).
37. Behrends, C., Sowa, M. E., Gygi, S. P. & Harper, J. W. Network organization of the human autophagy system. Nature 466, 68-76 (2010).
38. Young, A. R. et al. Autophagy mediates the mitotic senescence transition. Genes Dev. 23, 798-803 (2009).
39. Jung, C. H. et al. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol. Biol. Cell 20, 1992-2003 (2009).
40. Hosokawa, N. et al. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol. Biol. Cell 20, 1981-1991 (2009).
41. Lee, S. B. et al. ATG1, an autophagy regulator, inhibits cell growth by negatively regulating S6 kinase. EMBO Rep. 8, 360-365 (2007). (Pubitemid 46511036)
42. Kundu, M. et al. Ulk1 plays a critical role in the autophagic clearance of mitochondria and ribosomes during reticulocyte maturation. Blood 112, 1493-1502 (2008).
43. Fimia, G. M. et al. Ambra1 regulates autophagy and development of the nervous system. Nature 447, 1121-1125 (2007).
44. Kihara, A., Noda, T., Ishihara, N. & Ohsumi, Y. Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae. J. Cell Biol. 152, 519-530 (2001). (Pubitemid 34280235)
45. Itakura, E., Kishi, C., Inoue, K. & Mizushima, N. Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Mol. Biol. Cell 19, 5360-5372 (2008).
46. Sun, Q. et al. Identification of Barkor as a mammalian autophagy-specific factor for Beclin 1 and class III phosphatidylinositol 3-kinase. Proc. Natl Acad. Sci. USA 105, 19211-19216 (2008).
47. Zhong, Y. et al. Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. Nat. Cell Biol. 11, 468-476 (2009).
48. Takahashi, Y. et al. Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat. Cell Biol. 9, 1142-1151 (2007). (Pubitemid 47500490)
49. Backer, J. M. The regulation and function of class III PI3Ks: Novel roles for Vps34. Biochem. J. 410, 1-17 (2008). (Pubitemid 351300321)
50. Matsunaga, K. et al. Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat. Cell Biol. 11, 385-396 (2009).
51. Young, A. R. et al. Starvation and ULK1-dependent cycling of mammalian Atg9 between the TGN and endosomes. J. Cell Sci. 119, 3888-3900 (2006). (Pubitemid 44614440)
52. Yen, W. L., Legakis, J. E., Nair, U. & Klionsky, D. J. Atg27 is required for autophagy-dependent cycling of Atg9. Mol. Biol. Cell 18, 581-593 (2007). (Pubitemid 46213226)
53. Legakis, J. E., Yen, W. L. & Klionsky, D. J. A cycling protein complex required for selective autophagy. Autophagy 3, 422-432 (2007). (Pubitemid 47293723)
54. Tucker, K. A., Reggiori, F., Dunn, W. A., Jr & Klionsky, D. J. Atg23 is essential for the cytoplasm to vacuole targeting pathway and efficient autophagy but not pexophagy. J. Biol. Chem. 278, 48445-48452 (2003). (Pubitemid 37523300)
55. 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 6, 79-90 (2004). (Pubitemid 38089207)
56. Ropolo, A. et al. The pancreatitis-induced vacuole membrane protein 1 triggers autophagy in mammalian cells. J. Biol. Chem. 282, 37124-37133 (2007).
57. Axe, E. L. et al. Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J. Cell Biol. 182, 685-701 (2008).
58. Yla-Anttila, P., Vihinen, H., Jokitalo, E. & Eskelinen, E. L. 3D tomography reveals connections between the phagophore and endoplasmic reticulum. Autophagy 5, 1180-1185 (2009).
59. Tooze, S. A. & Yoshimori, T. The origin of the autophagosomal membrane. Nat. Cell Biol. 12, 831-835 (2010).
60. Pankiv, S. et al. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J. Biol. Chem. 282, 24131-24145 (2007). (Pubitemid 47328003)
61. Schweers, R. L. et al. NIX is required for programmed mitochondrial clearance during reticulocyte maturation. Proc. Natl Acad. Sci. USA 104, 19500-19505 (2007).
62. Amaravadi, R. K. et al. Principles and current strategies for targeting autophagy for cancer treatment. Clin. Cancer Res. 17, 654-666 (2011).
63. Jager, S. et al. Role for Rab7 in maturation of late autophagic vacuoles. J. Cell Sci. 117, 4837-4848 (2004). (Pubitemid 39433449)
64. Tanaka, Y. et al. Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice. Nature 406, 902-906 (2000). (Pubitemid 30664267)
65. Nakagawa, I. et al. Autophagy defends cells against invading group A Streptococcus. Science 306, 1037-1040 (2004). (Pubitemid 39482907)
66. Kuma, A. & Mizushima, N. Physiological role of autophagy as an intracellular recycling system: With an emphasis on nutrient metabolism. Semin. Cell Dev. Biol. 21, 683-690 (2010).
67. White, E. & DiPaola, R. S. The double-edged sword of autophagy modulation in cancer. Clin. Cancer Res. 15, 5308-5316 (2009).
68. Mathew, R., Karantza-Wadsworth, V. & White, E. Role of autophagy in cancer. Nat. Rev. Cancer 7, 961-967 (2007). (Pubitemid 350165856)
69. Levine, B. & Kroemer, G. Autophagy in the pathogenesis of disease. Cell 132, 27-42 (2008).
70. Harris, A. L. Hypoxia-A key regulatory factor in tumour growth. Nat. Rev. Cancer 2, 38-47 (2002). (Pubitemid 37328806)
71. Chau, B. N. & Wang, J. Y. Coordinated regulation of life and death by RB. Nat. Rev. Cancer 3, 130-138 (2003). (Pubitemid 37328880)
72. Lum, J. J. et al. Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell 120, 237-248 (2005). (Pubitemid 40174766)
73. Jin, S., DiPaola, R. S., Mathew, R. & White, E. Metabolic catastrophe as a means to cancer cell death. J. Cell Sci. 120, 379-383 (2007). (Pubitemid 46332501)
74. Liu, P., Cheng, H., Roberts, T. M. & Zhao, J. J. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat. Rev. Drug Discov. 8, 627-644 (2009).
75. Engelman, J. A. Targeting PI3K signalling in cancer: Opportunities, challenges and limitations. Nat. Rev. Cancer 9, 550-562 (2009).
76. Jin, S. & White, E. Role of autophagy in cancer: Management of metabolic stress. Autophagy 3, 28-31 (2007). (Pubitemid 46100707)
77. Jin, S. & White, E. Tumor suppression by autophagy through the management of metabolic stress. Autophagy 4, 563-566 (2008).
78. Maclean, K. H., Dorsey, F. C., Cleveland, J. L. & Kastan, M. B. Targeting lysosomal degradation induces p53-dependent cell death and prevents cancer in mouse models of lymphomagenesis. J. Clin. Invest. 118, 79-88 (2008).
79. Karantza-Wadsworth, V. et al. Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev. 21, 1621-1635 (2007). (Pubitemid 47026367)
80. Qu, X. et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J. Clin. Invest. 112, 1809-1820 (2003). (Pubitemid 38063704)
81. 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. USA 100, 15077-15082 (2003). (Pubitemid 37518019)
82. Qu, X. et al. Autophagy gene-dependent clearance of apoptotic cells during embryonic development. Cell 128, 931-946 (2007). (Pubitemid 46341412)
83. Mathew, R. et al. Autophagy suppresses tumorigenesis through elimination of p62. Cell 137, 1062-1075 (2009).
84. Kongara, S. et al. Autophagy regulates keratin 8 homeostasis in mammary epithelial cells and in breast tumors. Mol. Cancer Res. 8, 873-884 (2010).
85. Rubinsztein, D. C. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 443, 780-786 (2006). (Pubitemid 44622682)
86. Li, B. X. et al. The expression of beclin 1 is associated with favorable prognosis in stage IIIB colon cancers. Autophagy 5, 303-306 (2009).
87. Chen, Y., Lu, Y., Lu, C. & Zhang, L. Beclin-1 expression is a predictor of clinical outcome in patients with esophageal squamous cell carcinoma and correlated to hypoxia-inducible factor (HIF)-1a expression. Pathol. Oncol. Res. 15, 487-493 (2009).
88. Martin, A. P. et al. Inhibition of MCL-1 enhances lapatinib toxicity and overcomes lapatinib resistance via BAK-dependent autophagy. Cancer Biol. Ther. 8, 2084-2096 (2009).
89. Pirtoli, L. et al. The prognostic role of Beclin 1 protein expression in high-grade gliomas. Autophagy 5, 930-936 (2009).
90. Ding, Z. B. et al. Association of autophagy defect with a malignant phenotype and poor prognosis of hepatocellular carcinoma. Cancer Res. 68, 9167-9175 (2008).
91. Pattingre, S. et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122, 927-939 (2005). (Pubitemid 41345209)
92. Won, K. Y., Kim, G. Y., Kim, Y. W., Song, J. Y. & Lim, S. J. Clinicopathologic correlation of beclin-1 and bcl-2 expression in human breast cancer. Hum. Pathol. 41, 107-112 (2009).
93. Ahn, C. H. et al. Expression of beclin-1, an autophagy-related protein, in gastric and colorectal cancers. APMIS 115, 1344-1349 (2007).
94. Wan, X. B. et al. Elevated Beclin 1 expression is correlated with HIF-1a in predicting poor prognosis of nasopharyngeal carcinoma. Autophagy 6, 395-404 (2010).
95. Bellot, G. et al. Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol. Cell Biol. 29, 2570-2581 (2009).
96. Band, M., Joel, A., Hernandez, A. & Avivi, A. Hypoxia-induced BNIP3 expression and mitophagy: In vivo comparison of the rat and the hypoxia-tolerant mole rat, Spalax ehrenbergi. FASEB J. 23, 2327-2335 (2009).
97. Youle, R. J. & Narendra, D. P. Mechanisms of mitophagy. Nat. Rev. Mol. Cell Biol. 12, 9-14 (2011).
98. Park, J. et al. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 441, 1157-1161 (2006). (Pubitemid 43990737)
99. Cesari, R. et al. Parkin, a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25-q27. Proc. Natl Acad. Sci. USA 100, 5956-5961 (2003). (Pubitemid 36581860)
100. Poulogiannis, G. et al. PARK2 deletions occur frequently in sporadic colorectal cancer and accelerate adenoma development in Apc mutant mice. Proc. Natl Acad. Sci. USA 107, 15145-15150 (2010).
101. DeYoung, M. P., Horak, P., Sofer, A., Sgroi, D. & Ellisen, L. W. Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev. 22, 239-251 (2008).
102. Glick, D., Barth, S. & Macleod, K. F. Autophagy: Cellular and molecular mechanisms. J. Pathol. 221, 3-12 (2010).
103. Lazova, R., Klump, V. & Pawelek, J. Autophagy in cutaneous malignant melanoma. J. Cutan. Pathol. 37, 256-268 (2009).
104. Yoshioka, A. et al. LC3, an autophagosome marker, is highly expressed in gastrointestinal cancers. Int. J. Oncol. 33, 461-468 (2008).
105. Cao, C. et al. Inhibition of mammalian target of rapamycin or apoptotic pathway induces autophagy and radiosensitizes PTEN null prostate cancer cells. Cancer Res. 66, 10040-10047 (2006). (Pubitemid 44672057)
106. Alonso, M. M. et al. Delta-24-RGD in combination with RAD001 induces enhanced anti-glioma effect via autophagic cell death. Mol. Ther. 16, 487-493 (2008). (Pubitemid 351314987)
107. Takeuchi, H. et al. Synergistic augmentation of rapamycin-induced autophagy in malignant glioma cells by phosphatidylinositol 3-kinase/protein kinase B inhibitors. Cancer Res. 65, 3336-3346 (2005). (Pubitemid 40524618)
108. Paglin, S. et al. Rapamycin-sensitive pathway regulates mitochondrial membrane potential, autophagy, and survival in irradiated MCF-7 cells. Cancer Res. 65, 11061-11070 (2005). (Pubitemid 41713377)
109. Yazbeck, V. Y. et al. Temsirolimus downregulates p21 without altering cyclin D1 expression and induces autophagy and synergizes with vorinostat in mantle cell lymphoma. Exp. Hematol. 36, 443-450 (2008). (Pubitemid 351384743)
110. Crazzolara, R., Bradstock, K. F. & Bendall, L. J. RAD001 (Everolimus) induces autophagy in acute lymphoblastic leukemia. Autophagy 5, 727-728 (2009).
111. Alvero, A. B. et al. NV-128, a novel isoflavone derivative, induces caspase-independent cell death through the Akt/mammalian target of rapamycin pathway. Cancer 115, 3204-3216 (2009).
112. Adams, J. The development of proteasome inhibitors as anticancer drugs. Cancer Cell 5, 417-421 (2004). (Pubitemid 38610244)
113. Ding, W. X. et al. Oncogenic transformation confers a selective susceptibility to the combined suppression of the proteasome and autophagy. Mol. Cancer Ther. 8, 2036-2045 (2009).
114. Zhu, K., Dunner, K. Jr & McConkey, D. J. Proteasome inhibitors activate autophagy as a cytoprotective response in human prostate cancer cells. Oncogene 29, 451-462 (2010).
115. Pandey, U. B. et al. HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 447, 859-863 (2007). (Pubitemid 46920134)
116. Ertmer, A. et al. The anticancer drug imatinib induces cellular autophagy. Leukemia 21, 936-942 (2007). (Pubitemid 46672069)
117. Basciani, S. et al. Imatinib interferes with survival of multi drug resistant Kaposi's sarcoma cells. FEBS Lett. 581, 5897-5903 (2007). (Pubitemid 50009360)
118. Bilir, A. et al. Potentiation of cytotoxicity by combination of imatinib and chlorimipramine in glioma. Int. J. Oncol. 32, 829-839 (2008). (Pubitemid 351780593)
119. Gupta, A. et al. Autophagy inhibition and antimalarials promote cell death in gastrointestinal stromal tumor (GIST). Proc. Natl Acad. Sci. USA 107, 14333-14338 (2010).
120. Milano, V., Piao, Y., LaFortune, T. & de Groot, J. Dasatinib-induced autophagy is enhanced in combination with temozolomide in glioma. Mol. Cancer Ther. 8, 394-406 (2009).
121. Bellodi, C. et al. Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells. J. Clin. Invest. 119, 1109-1123 (2009).
122. Mishima, Y. et al. Autophagy and autophagic cell death are next targets for elimination of the resistance to tyrosine kinase inhibitors. Cancer Sci. 99, 2200-2208 (2008).
123. Martin, A. P. et al. BCL-2 family inhibitors enhance histone deacetylase inhibitor and sorafenib lethality via autophagy and overcome blockade of the extrinsic pathway to facilitate killing. Mol. Pharmacol. 76, 327-341 (2009).
124. Shao, Y., Gao, Z., Marks, P. A. & Jiang, X. Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. Proc. Natl Acad. Sci. USA 101, 18030-18035 (2004). (Pubitemid 40054069)
125. Yamamoto, S. et al. Suberoylanilide hydroxamic acid (SAHA) induces apoptosis or autophagy-Associated cell death in chondrosarcoma cell lines. Anticancer Res. 28, 1585-1591 (2008). (Pubitemid 351892934)
126. Ellis, L. et al. The histone deacetylase inhibitors LAQ824 and LBH589 do not require death receptor signaling or a functional apoptosome to mediate tumor cell death or therapeutic efficacy. Blood 114, 380-393 (2009).
127. Turzanski, J., Daniels, I. & Haynes, A. P. Involvement of macroautophagy in the caspase-independent killing of Burkitt lymphoma cell lines by rituximab. Br. J. Haematol. 145, 137-140 (2009).
128. Giannopoulou, E., Antonacopoulou, A., Matsouka, P. & Kalofonos, H. P. Autophagy: Novel action of panitumumab in colon cancer. Anticancer Res. 29, 5077-5082 (2009).
129. Bursch, W. et al. 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 (1996). (Pubitemid 26280381)
130. Samaddar, J. S. et al. A role for macroautophagy in protection against 4-hydroxytamoxifen-induced cell death and the development of antiestrogen resistance. Mol. Cancer Ther. 7, 2977-2987 (2008).
131. Pan, J. & Yeung, S. C. Recent advances in understanding the antineoplastic mechanisms of farnesyltransferase inhibitors. Cancer Res. 65, 9109-9112 (2005). (Pubitemid 41507967)
132. Pan, J. et al. Autophagy induced by farnesyltransferase inhibitors in cancer cells. Cancer Biol. Ther. 7, 1679-1684 (2008).
133. Albert, J. M. et al. Inhibition of poly(ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models. Clin. Cancer Res. 13, 3033-3042 (2007). (Pubitemid 46849580)
134. Munoz-Gamez, J. A. et al. PARP-1 is involved in autophagy induced by DNA damage. Autophagy 5, 61-74 (2009).
135. Hoyer-Hansen, M., Bastholm, L., Mathiasen, I. S., Elling, F. & Jaattela, M. Vitamin D analog EB1089 triggers dramatic lysosomal changes and Beclin 1-mediated autophagic cell death. Cell Death Differ. 12, 1297-1309 (2005). (Pubitemid 41486100)
136. Demasters, G., Di, X., Newsham, I., Shiu, R. & Gewirtz, D. A. Potentiation of radiation sensitivity in breast tumor cells by the vitamin D3 analogue, EB 1089, through promotion of autophagy and interference with proliferative recovery. Mol. Cancer Ther. 5, 2786-2797 (2006). (Pubitemid 44849005)
137. Hoyer-Hansen, M. et al. Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-beta, and Bcl-2. Mol. Cell 25, 193-205 (2007). (Pubitemid 46109606)
138. Kanzawa, T., Kondo, Y., Ito, H., Kondo, S. & Germano, I. Induction of autophagic cell death in malignant glioma cells by arsenic trioxide. Cancer Res. 63, 2103-2108 (2003). (Pubitemid 36538613)
139. Kanzawa, T. et al. Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein BNIP3. Oncogene 24, 980-991 (2005). (Pubitemid 40313875)
140. Qian, W., Liu, J., Jin, J., Ni, W. & Xu, W. Arsenic trioxide induces not only apoptosis but also autophagic cell death in leukemia cell lines via up-regulation of Beclin-1. Leuk. Res. 31, 329-339 (2007). (Pubitemid 46073178)
141. Scarlatti, F. et al. Resveratrol induces growth inhibition and apoptosis in metastatic breast cancer cells via de novo ceramide signaling. FASEB J. 17, 2339-2341 (2003). (Pubitemid 39561486)
142. Scarlatti, F., Maffei, R., Beau, I., Codogno, P. & Ghidoni, R. Role of non-canonical Beclin 1-independent autophagy in cell death induced by resveratrol in human breast cancer cells. Cell Death Differ. 15, 1318-1329 (2008). (Pubitemid 351984760)
143. Li, J., Qin, Z. & Liang, Z. The prosurvival role of autophagy in Resveratrol-induced cytotoxicity in human U251 glioma cells. BMC Cancer 9, 215 (2009).
144. Stein, M. et al. Targeting tumor metabolism with 2-deoxyglucose in patients with castrate-resistant prostate cancer and advanced malignancies. Prostate 70, 1388-1394 (2010).
145. Poole, B. & Ohkuma, S. Effect of weak bases on the intralysosomal pH in mouse peritoneal macrophages. J. Cell Biol. 90, 665-669 (1981). (Pubitemid 12254922)
146. Glaumann, H. & Ahlberg, J. Comparison of different autophagic vacuoles with regard to ultrastructure, enzymatic composition, and degradation capacity-formation of crinosomes. Exp. Mol. Pathol. 47, 346-362 (1987). (Pubitemid 18018899)
147. Amaravadi, R. K. et al. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J. Clin. Invest. 117, 326-336 (2007). (Pubitemid 46203961)
148. Carew, J. S. et al. Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-Abl-mediated drug resistance. Blood 110, 313-322 (2007). (Pubitemid 47026849)
149. Sotelo, J., Briceno, E. & Lopez-Gonzalez, M. A. Adding chloroquine to conventional treatment for glioblastoma multiforme: A randomized, double-blind, placebo-controlled trial. Ann. Intern. Med. 144, 337-343 (2006). (Pubitemid 46768188)
150. Lu, Z. et al. The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human ovarian cancer cells. J. Clin. Invest. 118, 3917-3929 (2008).
151. Amaravadi, R. K. & Thompson, C. B. The roles of therapy-induced autophagy and necrosis in cancer treatment. Clin. Cancer Res. 13, 7271-7279 (2007).
152. Kabeya, Y. et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 19, 5720-5728 (2000).
153. Mizushima, N., Yoshimori, T. & Levine, B. Methods in mammalian autophagy research. Cell 140, 313-326 (2010).
154. Klionsky, D. J. et al. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 4, 151-175 (2008). (Pubitemid 351231180)