Autophagy and cell death to target cancer cells: Exploiting synthetic lethality as cancer therapies

Advances in Experimental Medicine and Biology

Volumn 772, Issue , 2014, Pages 167-188

  Reyjal, Julie ^a,b   Cormier, Kevin ^a,b   Turcotte, Sandra ^a,b  

^a UNIVERSITÉ DE MONCTON   (Canada)

^b ATLANTIC CANCER RESEARCH INSTITUTE   (Canada)

Author keywords

Autophagy; Cancer; Cell death; Renal cell carcinoma; Synthetic lethality; Targeted therapy; von Hippel Lindau

Indexed keywords

BECLIN 1; CHLOROQUINE; EVEROLIMUS; FLUOROURACIL; HYDROXYCHLOROQUINE; LUCANTHONE; OBATOCLAX; PROTEIN BCL 2; TEMOZOLOMIDE; TEMSIROLIMUS; VORINOSTAT;

ACUTE LYMPHOBLASTIC LEUKEMIA; ADVANCED CANCER; ANTINEOPLASTIC ACTIVITY; AUTOPHAGOSOME; AUTOPHAGY; CANCER CELL; CANCER COMBINATION CHEMOTHERAPY; CANCER GROWTH; CANCER SURVIVAL; CANCER THERAPY; CELL DEATH; CELL KILLING; CELL PROLIFERATION; CELL SURVIVAL; CELL VIABILITY; CHEMORADIOTHERAPY; CHRONIC MYELOID LEUKEMIA; CLINICAL TRIAL (TOPIC); COLON CANCER; CONFERENCE PAPER; DRUG EFFICACY; DRUG MECHANISM; DRUG POTENTIATION; DRUG RESPONSE; DRUG SAFETY; ENDOSOME; GENE MUTATION; GLIOBLASTOMA; HUMAN; KIDNEY CANCER; KIDNEY CARCINOMA; LUNG NON SMALL CELL CANCER; LYSOSOME; NONHUMAN; ONCOGENE; OVERALL SURVIVAL; PANCREAS CANCER; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; PROTEIN TARGETING; SURVIVAL RATE; TUMOR GROWTH; TUMOR MICROENVIRONMENT; TUMOR SUPPRESSOR GENE; VHL GENE;

ANIMALS; ANTINEOPLASTIC AGENTS; AUTOPHAGY; HUMANS; LYSOSOMES; MOLECULAR TARGETED THERAPY; NEOPLASMS; PHAGOSOMES; SIGNAL TRANSDUCTION;

EID: 84934440934     PISSN: 00652598     EISSN: None     Source Type: Book Series    
DOI: 10.1007/978-1-4614-5915-6_8     Document Type: Conference Paper

References (129)

1. Aita VM, Liang XH, Murty V V, Pincus DL, Yu W, Cayanis E, Kalachikov S, Gilliam TC, Levine B (1999) Cloning and genomic organization of beclin 1, a candidate tumor suppressor gene on chromosome 17q21. Genomics 59(1):59-65. doi: 10.1006/geno.1999.5851
2. Amaravadi RK, Lippincott-Schwartz J, Yin XM, Weiss WA, Takebe N, Timmer W, DiPaola RS, Lotze MT, White E (2011) Principles and current strategies for targeting autophagy for cancer treatment. Clin Cancer Res 17(4):654-666. doi: 10.1158/1078-0432.CCR-10-2634
3. Amelio I, Melino G, Knight RA (2011) Cell death pathology: cross-talk with autophagy and its clinical implications. Biochem Biophys Res Commun 414(2):277-281. doi: 10.1016/j. bbrc.2011.09.080
4. Ansari J, Palmer DH, Rea DW, Hussain SA (2009) Role of tyrosine kinase inhibitors in lung cancer. Anticancer Agents Med Chem 9(5):569-575
5. Arena G, Gelmetti V, Torosantucci L, Vignone D, Lamorte G, De Rosa P, Cilia E, Jonas EA, Valente EM (2013) PINK1 protects against cell death induced by mitochondrial depolarization, by phosphorylating Bcl-xL and impairing its pro-apoptotic cleavage. Cell Death Differ. doi: 10.1038/cdd.2013.19
6. Axe EL, Walker SA, Manifava M, Chandra P, Roderick HL, Habermann A, Griffiths G, Ktistakis NT (2008) Autophagosome formation from membrane compartments enriched in phosphati-dylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J Cell Biol 182(4):685-701. doi: 10.1083/jcb.200803137
7. Bar-Peled L, Schweitzer LD, Zoncu R, Sabatini DM (2012) Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1. Cell 150(6):1196-1208. doi: 10.1016/j. cell.2012.07.032
8. Bellot G, Garcia-Medina R, Gounon P, Chiche J, Roux D, Pouyssegur J, Mazure NM (2009) Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol Cell Biol 29(10):2570-2581. doi: 10.1128/MCB.00166-09
9. Bommi-Reddy A, Almeciga I, Sawyer J, Geisen C, Li W, Harlow E, Kaelin WG Jr, Grueneberg DA (2008) Kinase requirements in human cells: III. Altered kinase requirements in VHL-/-cancer cells detected in a pilot synthetic lethal screen. Proc Natl Acad Sci USA 105(43):16484-16489. doi: 10.1073/pnas.0806574105
10. Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434(7035):913-917. doi: 10.1038/nature03443
11. Carew JS, Nawrocki ST, Kahue CN, Zhang H, Yang C, Chung L, Houghton JA, Huang P, Giles FJ, Cleveland JL (2007) Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-Abl-mediated drug resistance. Blood 110(1):313-322. doi: 10.1182/blood-2006-10-050260
12. Carew JS, Espitia CM, Esquivel JA 2nd, Mahalingam D, Kelly KR, Reddy G, Giles FJ, Nawrocki ST (2011) Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem 286(8):6602-6613. doi: 10.1074/jbc.M110.151324
13. Casey G, Plummer S, Hoeltge G, Scanlon D, Fasching C, Stanbridge EJ (1993) Functional evidence for a breast cancer growth suppressor gene on chromosome 17. Hum Mol Genet 2(11):1921-1927
14. Chan DA, Giaccia AJ (2011) Harnessing synthetic lethal interactions in anticancer drug discovery. Nat Rev Drug Discov 10(5):351-364. doi: 10.1038/nrd3374
15. Chan DA, Sutphin PD, Nguyen P, Turcotte S, Lai EW, Banh A, Reynolds GE, Chi JT, Wu J, SolowCordero DE, Bonnet M, Flanagan JU, Bouley DM, Graves EE, Denny WA, Hay MP, Giaccia AJ (2011) Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality. Sci Transl Med 3(94):94ra70. doi: 10.1126/scitranslmed.3002394
16. Chen Y, Lu Y, Lu C, Zhang L (2009) Beclin-1 expression is a predictor of clinical outcome in patients with esophageal squamous cell carcinoma and correlated to hypoxia-inducible factor (HIF)-1alpha expression. Pathol Oncol Res 15(3):487-493. doi: 10.1007/s12253-008-9143-8
17. Clarkson J, Erasmus DA (1984) Schistosoma mansoni: an in vivo study of drug-induced autoph-agy in the gastrodermis. J Helminthol 58(1):59-68
18. Copple IM, Lister A, Obeng AD, Kitteringham NR, Jenkins RE, Layfield R, Foster BJ, Goldring CE, Park BK (2010) Physical and functional interaction of sequestosome 1 with Keap1 regulates the Keap1-Nrf2 cell defense pathway. J Biol Chem 285(22):16782-16788. doi: 10.1074/jbc.M109.096545
19. Crazzolara R, Bradstock KF, Bendall LJ (2009) RAD001 (Everolimus) induces autophagy in acute lymphoblastic leukemia. Autophagy 5(5):727-728
20. Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, Mukherjee C, Shi Y, Gelinas C, Fan Y, Nelson DA, Jin S, White E (2006) Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 10(1):51-64. doi: 10.1016/j.ccr.2006.06.001
21. Erlich S, Mizrachy L, Segev O, Lindenboim L, Zmira O, Adi-Harel S, Hirsch JA, Stein R, Pinkas-Kramarski R (2007) Differential interactions between Beclin 1 and Bcl-2 family members. Autophagy 3(6):561-568
22. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM (2007a) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356(2):125-134. doi: 10.1056/NEJMoa060655
23. Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N (2007b) Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370(9605):2103-2111. doi: 10.1016/S0140-6736(07)61904-7
24. Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, Martin NM, Jackson SP, Smith GC, Ashworth A (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434(7035):917-921. doi: 10.1038/nature03445
25. Feng Z (2010) p53 regulation of the IGF-1/AKT/mTOR pathways and the endosomal compartment. Cold Spring Harb Perspect Biol 2(2):a001057. doi: 10.1101/cshperspect.a001057
26. Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, O'Connor MJ, Ashworth A, Carmichael J, Kaye SB, Schellens JH, de Bono JS (2009) Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361(2):123-134. doi: 10.1056/NEJMoa0900212
27. Fujii S, Mitsunaga S, Yamazaki M, Hasebe T, Ishii G, Kojima M, Kinoshita T, Ueno T, Esumi H, Ochiai A (2008) Autophagy is activated in pancreatic cancer cells and correlates with poor patient outcome. Cancer Sci 99(9):1813-1819. doi: 10.1111/j.1349-7006.2008.00893.x
28. Gu J, Ruppen ME, Cai P (2005) lipase-catalyzed regioselective esterification of rapamycin: synthesis of temsirolimus (CCI-779). Org Lett 7(18):3945-3948. doi: 10.1021/ol0514395
29. Guo JY, Chen HY, Mathew R, Fan J, Strohecker AM, Karsli-Uzunbas G, Kamphorst JJ, Chen G, Lemons JM, Karantza V, Coller HA, Dipaola RS, Gelinas C, Rabinowitz JD, White E (2011) Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev 25(5):460-470. doi: 10.1101/gad.2016311
30. Hailey DW, Rambold AS, Satpute-Krishnan P, Mitra K, Sougrat R, Kim PK, Lippincott-Schwartz J (2010) Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell 141(4):656-667. doi: 10.1016/j.cell.2010.04. 009
31. Hall JM, Friedman L, Guenther C, Lee MK, Weber JL, Black DM, King MC (1992) Closing in on a breast cancer gene on chromosome 17q. Am J Hum Genet 50(6):1235-1242
32. Hartman JL, Garvik B, Hartwell L (2001) Principles for the buffering of genetic variation. Science 291(5506):1001-1004
33. Hartwell LH, Szankasi P, Roberts CJ, Murray AW, Friend SH (1997) Integrating genetic approaches into the discovery of anticancer drugs. Science 278(5340):1064-1068
34. Hayashi-Nishino M, Fujita N, Noda T, Yamaguchi A, Yoshimori T, Yamamoto A (2009) A subdo-main of the endoplasmic reticulum forms a cradle for autophagosome formation. Nat Cell Biol 11(12):1433-1437. doi: 10.1038/ncb1991
35. Heidari N, Hicks MA, Harada H (2010) GX15-070 (obatoclax) overcomes glucocorticoid resistance in acute lymphoblastic leukemia through induction of apoptosis and autophagy. Cell Death Dis 1:e76. doi: 10.1038/cddis.2010.53
36. Heuser J (1989) Changes in lysosome shape and distribution correlated with changes in cytoplas-mic pH. J Cell Biol 108(3):855-864
37. Hirata H, Hinoda Y, Ueno K, Nakajima K, Ishii N, Dahiya R (2012) MicroRNA-1826 directly targets beta-catenin (CTNNB1) and MEK1 (MAP2K1) in VHL-inactivated renal cancer. Carcinogenesis 33(3):501-508. doi: 10.1093/carcin/bgr302
38. Horbinski C, Mojesky C, Kyprianou N (2010) Live free or die: tales of homeless (cells) in cancer. Am J Pathol 177(3):1044-1052. doi: 10.2353/ajpath.2010.091270
39. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ (2007) Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356(22):2271-2281. doi: 10.1056/NEJMoa066838
40. Hutchinson L (2010) Targeted therapies: PARP inhibitor olaparib is safe and effective in patients with BRCA1 and BRCA2 mutations. Nat Rev Clin Oncol 7(10):549. doi: 10.1038/nrclinonc.2010.143
41. Inami Y, Waguri S, Sakamoto A, Kouno T, Nakada K, Hino O, Watanabe S, Ando J, Iwadate M, Yamamoto M, Lee MS, Tanaka K, Komatsu M (2011) Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells. J Cell Biol 193(2):275-284. doi: 10.1083/jcb.201102031
42. Janku F, McConkey DJ, Hong DS, Kurzrock R (2011) Autophagy as a target for anticancer therapy. Nat Rev Clin Oncol 8(9):528-539. doi: 10.1038/nrclinonc.2011.71
43. Jiang H, Reinhardt HC, Bartkova J, Tommiska J, Blomqvist C, Nevanlinna H, Bartek J, Yaffe MB, Hemann MT (2009) The combined status of ATM and p53 link tumor development with therapeutic response. Genes Dev 23(16):1895-1909. doi: 10.1101/gad.1815309
44. Jung CH, Jun CB, Ro SH, Kim YM, Otto NM, Cao J, Kundu M, Kim DH (2009) ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell 20(7):1992-2003. doi: 10.1091/mbc.E08-12-1249
45. Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, Kominami E, Ohsumi Y, Yoshimori T (2000) LC3, a mammalian homologue of yeast Apg8p, is localized in autophago-some membranes after processing. EMBO J 19(21):5720-5728. doi: 10.1093/emboj/19.21.5720
46. Kaelin WG Jr (2005) The concept of synthetic lethality in the context of anticancer therapy. Nat Rev Cancer 5(9):689-698
47. Kaelin WG Jr (2008) The von Hippel-Lindau tumour suppressor protein: O 2 sensing and cancer. Nat Rev Cancer 8(11):865-873
48. Kang R, Zeh HJ, Lotze MT, Tang D (2011) The Beclin 1 network regulates autophagy and apop-tosis. Cell Death Differ 18(4):571-580. doi: 10.1038/cdd.2010.191
49. Kenific CM, Thorburn A, Debnath J (2010) Autophagy and metastasis: another double-edged sword. Curr Opin Cell Biol 22(2):241-245. doi: 10.1016/j.ceb.2009.10.008
50. Kim HS, Lee SH, Do SI, Lim SJ, Park YK, Kim YW (2011) Clinicopathologic correlation of beclin-1 expression in pancreatic ductal adenocarcinoma. Pathol Res Pract 207(4):247-252. doi: 10.1016/j.prp.2011.02.007
51. Klionsky DJ, Emr SD (2000) Autophagy as a regulated pathway of cellular degradation. Science 290(5497):1717-1721
52. Korolchuk VI, Rubinsztein DC (2011) Regulation of autophagy by lysosomal positioning. Autophagy 7(8):927-928
53. Korolchuk VI, Saiki S, Lichtenberg M, Siddiqi FH, Roberts EA, Imarisio S, Jahreiss L, Sarkar S, Futter M, Menzies FM, O'Kane CJ, Deretic V, Rubinsztein DC (2011) Lysosomal positioning coordinates cellular nutrient responses. Nat Cell Biol 13(4):453-460. doi: 10.1038/ncb2204
54. Kreuzaler P, Watson CJ (2012) Killing a cancer: what are the alternatives? Nat Rev Cancer 12(6):411-424. doi: 10.1038/nrc3264
55. Kroemer G, Marino G, Levine B (2010) Autophagy and the integrated stress response. Mol Cell 40(2):280-293. doi: 10.1016/j.molcel.2010.09.023
56. Lamb CA, Dooley HC, Tooze SA (2013) Endocytosis and autophagy: shared machinery for degradation. Bioessays 35(1):34-45. doi: 10.1002/bies.201200130
57. Lau A, Wang XJ, Zhao F, Villeneuve NF, Wu T, Jiang T, Sun Z, White E, Zhang DD (2010) A noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62. Mol Cell Biol 30(13):3275-3285. doi: 10.1128/MCB.00248-10
58. Lee SJ, Kim HP, Jin Y, Choi AM, Ryter SW (2011) Beclin 1 deficiency is associated with increased hypoxia-induced angiogenesis. Autophagy 7(8):829-839
59. Levine B, Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132(1):27-42
60. Li BX, Li CY, Peng RQ, Wu XJ, Wang HY, Wan DS, Zhu XF, Zhang XS (2009) The expression of beclin 1 is associated with favorable prognosis in stage IIIB colon cancers. Autophagy 5(3):303-306
61. Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, Levine B (1999) Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402(6762):672-676. doi: 10.1038/45257
62. Liang C, Lee JS, Inn KS, Gack MU, Li Q, Roberts EA, Vergne I, Deretic V, Feng P, Akazawa C, Jung JU (2008) Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophago-some maturation and endocytic trafficking. Nat Cell Biol 10(7):776-787. doi: 10.1038/ncb1740
63. Luo J, Emanuele MJ, Li D, Creighton CJ, Schlabach MR, Westbrook TF, Wong KK, Elledge SJ (2009) A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 137(5):835-848. doi: 10.1016/j.cell.2009.05.006
64. Mah LY, Ryan KM (2012) Autophagy and cancer. Cold Spring Harb Perspect Biol 4(1):a008821. doi: 10.1101/cshperspect.a008821
65. Maher ER (2004) Von Hippel-Lindau disease. Curr Mol Med 4(8):833-842
66. Maiuri MC, Zalckvar E, Kimchi A, Kroemer G (2007) Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol 8(9):741-752. doi: 10.1038/nrm2239
67. 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/autopha-gin-3. J Biol Chem 282(25):18573-18583. doi: 10.1074/jbc.M701194200
68. Mathew R, Kongara S, Beaudoin B, Karp CM, Bray K, Degenhardt K, Chen G, Jin S, White E (2007) Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev 21(11):1367-1381. doi: 10.1101/gad.1545107
69. Mathew R, Karp CM, Beaudoin B, Vuong N, Chen G, Chen HY, Bray K, Reddy A, Bhanot G, Gelinas C, Dipaola RS, Karantza-Wadsworth V, White E (2009) Autophagy suppresses tumori-genesis through elimination of p62. Cell 137(6):1062-1075. doi: 10.1016/j.cell.2009.03.048
70. McAfee Q, Zhang Z, Samanta A, Levi SM, Ma XH, Piao S, Lynch JP, Uehara T, Sepulveda AR, Davis LE, Winkler JD, Amaravadi RK (2012) Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency. Proc Natl Acad Sci USA 109(21):8253-8258. doi: 10.1073/pnas.1118193109
71. McCoy F, Hurwitz J, McTavish N, Paul I, Barnes C, O'Hagan B, Odrzywol K, Murray J, Longley D, McKerr G, Fennell DA (2010) Obatoclax induces Atg7-dependent autophagy independent of beclin-1 and BAX/BAK. Cell Death Dis 1:e108. doi: 10.1038/cddis.2010.86
72. Miao Y, Zhang Y, Chen Y, Chen L, Wang F (2010) GABARAP is overexpressed in colorectal carcinoma and correlates with shortened patient survival. Hepatogastroenterology 57(98):257-261
73. Mizushima N (2010) The role of the Atg1/ULK1 complex in autophagy regulation. Curr Opin Cell Biol 22(2):132-139. doi: 10.1016/j.ceb.2009.12.004
74. Mizushima N, Sugita H, Yoshimori T, Ohsumi Y (1998) A new protein conjugation system in human. The counterpart of the yeast Apg12p conjugation system essential for autophagy. J Biol Chem 273(51):33889-33892
75. Mizushima N, Yoshimori T, Ohsumi Y (2011) The role of Atg proteins in autophagosome formation. Annu Rev Cell Dev Biol 27:107-132. doi: 10.1146/annurev-cellbio-092910-154005
76. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada clinical trials group. J Clin Oncol 25(15):1960-1966. doi: 10.1200/JCO.2006.07.9525
77. Motzer RJ, Bander NH, Nanus DM (1996) Renal-cell carcinoma. N Engl J Med 335(12):865-875. doi: 10.1056/NEJM199609193351207
78. Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, Ginsberg MS, Kim ST, Baum CM, DePrimo SE, Li JZ, Bello CL, Theuer CP, George DJ, Rini BI (2006) Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 24(1):16-24. doi: 10.1200/JCO.2005.02.2574
79. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA (2007) Sunitinib versus inter-feron alfa in metastatic renal-cell carcinoma. N Engl J Med 356(2):115-124. doi: 10.1056/NEJMoa065044
80. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grunwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A (2008) Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372(9637):449-456. doi: 10.1016/S0140-6736(08)61039-9
81. Nickerson ML, Jaeger E, Shi Y, Durocher JA, Mahurkar S, Zaridze D, Matveev V, Janout V, Kollarova H, Bencko V, Navratilova M, Szeszenia-Dabrowska N, Mates D, Mukeria A, Holcatova I, Schmidt LS, Toro JR, Karami S, Hung R, Gerard GF, Linehan WM, Merino M, Zbar B, Boffetta P, Brennan P, Rothman N, Chow WH, Waldman FM, Moore LE (2008) Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors. Clin Cancer Res 14(15):4726-4734
82. O'Reilly T, McSheehy PM, Wartmann M, Lassota P, Brandt R, Lane HA (2011) Evaluation of the mTOR inhibitor, everolimus, in combination with cytotoxic antitumor agents using human tumor models in vitro and in vivo. Anticancer Drugs 22(1):58-78. doi: 10.1097/CAD.0b013e3283400a20
83. Orsi A, Razi M, Dooley HC, Robinson D, Weston AE, Collinson LM, Tooze SA (2012) Dynamic and transient interactions of Atg9 with autophagosomes, but not membrane integration, are required for autophagy. Mol Biol Cell 23(10):1860-1873. doi: 10.1091/mbc.E11-09-0746
84. Ouyang L, Shi Z, Zhao S, Wang FT, Zhou TT, Liu B, Bao JK (2012) Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis. Cell Prolif 45(6):487-498. doi: 10.1111/j.1365-2184.2012. 00845.x
85. Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H, Overvatn A, Bjorkoy G, Johansen T (2007) p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem 282(33):24131-24145. doi: 10.1074/jbc. M702824200
86. Parikh B, Advani S (1996) Pattern of second primary neoplasms following breast cancer. J Surg Oncol 63(3):179-182. doi: 10.1002/(SICI)1096-9098(199611) 63:33.0.CO;2-A
87. Patard JJ, Rioux-Leclercq N, Masson D, Zerrouki S, Jouan F, Collet N, Dubourg C, Lobel B, Denis M, Fergelot P (2009) Absence of VHL gene alteration and high VEGF expression are associated with tumour aggressiveness and poor survival of renal-cell carcinoma. Br J Cancer 101(8):1417-1424
88. Patel PH, Chadalavada RS, Chaganti RS, Motzer RJ (2006) Targeting von Hippel-Lindau pathway in renal cell carcinoma. Clin Cancer Res 12(24):7215-7220
89. Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, Packer M, Schneider MD, Levine B (2005) Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122(6):927-939. doi: 10.1016/j.cell.2005.07.002
90. Pattingre S, Bauvy C, Carpentier S, Levade T, Levine B, Codogno P (2009) Role of JNK1-dependent Bcl-2 phosphorylation in ceramide-induced macroautophagy. J Biol Chem 284(5):2719-2728. doi: 10.1074/jbc.M805920200
91. Pena-Llopis S, Vega-Rubin-de-Celis S, Schwartz JC, Wolff NC, Tran TA, Zou L, Xie XJ, Corey DR, Brugarolas J (2011) Regulation of TFEB and V-ATPases by mTORC1. EMBO J 30(16):3242-3258. doi: 10.1038/emboj.2011.257
92. Peralta ER, Martin BC, Edinger AL (2010) Differential effects of TBC1D15 and mammalian Vps39 on Rab7 activation state, lysosomal morphology, and growth factor dependence. J Biol Chem 285(22):16814-16821. doi: 10.1074/jbc.M110.111633
93. Petermann E, Keil C, Oei SL (2005) Importance of poly(ADP-ribose) polymerases in the regulation of DNA-dependent processes. Cell Mol Life Sci 62(7-8):731-738. doi: 10.1007/s00018-004-4504-2
94. Poulogiannis G, McIntyre RE, Dimitriadi M, Apps JR, Wilson CH, Ichimura K, Luo F, Cantley LC, Wyllie AH, Adams DJ, Arends MJ (2010) PARK2 deletions occur frequently in sporadic colorectal cancer and accelerate adenoma development in Apc mutant mice. Proc Natl Acad Sci USA 107(34):15145-15150. doi: 10.1073/pnas.1009941107
95. Puyol M, Martin A, Dubus P, Mulero F, Pizcueta P, Khan G, Guerra C, Santamaria D, Barbacid M (2010) A synthetic lethal interaction between K-Ras oncogenes and Cdk4 unveils a therapeutic strategy for non-small cell lung carcinoma. Cancer Cell 18(1):63-73. doi: 10.1016/j. ccr.2010.05.025
96. Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, Rosen J, Eskelinen EL, Mizushima N, Ohsumi Y, Cattoretti G, Levine B (2003) Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest 112(12):1809-1820. doi: 10.1172/JCI20039
97. Ravikumar B, Moreau K, Jahreiss L, Puri C, Rubinsztein DC (2010) Plasma membrane contributes to the formation of pre-autophagosomal structures. Nat Cell Biol 12(8):747-757. doi: 10.1038/ncb2078
98. Reggiori F, Komatsu M, Finley K, Simonsen A (2012) Selective types of autophagy. Int J Cell Biol 2012:156272. doi: 10.1155/2012/156272
99. Rubinsztein DC, Codogno P, Levine B (2012) Autophagy modulation as a potential therapeutic target for diverse diseases. Nat Rev Drug Discov 11(9):709-730. doi: 10.1038/nrd3802
100. Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM (2010) Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141(2):290-303. doi: 10.1016/j.cell.2010.02.024
101. Sardiello M, Palmieri M, di Ronza A, Medina DL, Valenza M, Gennarino VA, Di Malta C, Donaudy F, Embrione V, Polishchuk RS, BanfiS, Parenti G, Cattaneo E, Ballabio A (2009) A gene network regulating lysosomal biogenesis and function. Science 325(5939):473-477. doi: 10.1126/science.1174447
102. Sarthy AV, Morgan-Lappe SE, Zakula D, Vernetti L, Schurdak M, Packer JC, Anderson MG, Shirasawa S, Sasazuki T, Fesik SW (2007) Survivin depletion preferentially reduces the survival of activated K-Ras-transformed cells. Mol Cancer Ther 6(1):269-276. doi: 10.1158/1535-7163.MCT-06-0560
103. Sasaki K, Tsuno NH, Sunami E, Tsurita G, Kawai K, Okaji Y, Nishikawa T, Shuno Y, Hongo K, Hiyoshi M, Kaneko M, Kitayama J, Takahashi K, Nagawa H (2010) Chloroquine potentiates the anti-cancer effect of 5-fluorouracil on colon cancer cells. BMC Cancer 10:370. doi: 10.1186/1471-2407-10-370
104. Scholl C, Frohling S, Dunn IF, Schinzel AC, Barbie DA, Kim SY, Silver SJ, Tamayo P, Wadlow RC, Ramaswamy S, Dohner K, Bullinger L, Sandy P, Boehm JS, Root DE, Jacks T, Hahn WC, Gilliland DG (2009) Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells. Cell 137(5):821-834. doi: 10.1016/j.cell.2009.03.017
105. Settembre C, Di Malta C, Polito VA, Garcia Arencibia M, Vetrini F, Erdin S, Erdin SU, Huynh T, Medina D, Colella P, Sardiello M, Rubinsztein DC, Ballabio A (2011) TFEB links autophagy to lysosomal biogenesis. Science 332(6036):1429-1433. doi: 10.1126/science.1204592
106. Settembre C, Zoncu R, Medina DL, Vetrini F, Erdin S, Huynh T, Ferron M, Karsenty G, Vellard MC, Facchinetti V, Sabatini DM, Ballabio A (2012) A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J 31(5):1095-1108. doi: 10.1038/emboj.2012.32
107. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston D, Bezjak A, Clark G, Santabarbara P, Seymour L (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353(2):123-132. doi: 10.1056/NEJMoa050753
108. Sun Q, Westphal W, Wong KN, Tan I, Zhong Q (2010) Rubicon controls endosome maturation as a Rab7 effector. Proc Natl Acad Sci USA 107(45):19338-19343. doi:10.1073/pnas.1010554107
109. Takamura A, Komatsu M, Hara T, Sakamoto A, Kishi C, Waguri S, Eishi Y, Hino O, Tanaka K, Mizushima N (2011) Autophagy-deficient mice develop multiple liver tumors. Genes Dev 25(8):795-800. doi: 10.1101/gad.2016211
110. Takeshige K, Baba M, Tsuboi S, Noda T, Ohsumi Y (1992) Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction. J Cell Biol 119(2):301-311
111. Torrance CJ, Agrawal V, Vogelstein B, Kinzler KW (2001) Use of isogenic human cancer cells for high-throughput screening and drug discovery. Nat Biotechnol 19(10):940-945. doi: 10.1038/nbt1001-940
112. Turcotte S, Giaccia AJ (2010) Targeting cancer cells through autophagy for anticancer therapy. Curr Opin Cell Biol 22(2):246-251. doi: 10.1016/j.ceb.2009.12.007
113. Turcotte S, Chan DA, Sutphin PD, Hay MP, Denny WA, Giaccia AJ (2008) A molecule targeting VHL-deficient renal cell carcinoma that induces autophagy. Cancer Cell 14(1):90-102. doi: 10.1016/j.ccr.2008.06.004
114. Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, Friedlander M, Arun B, Loman N, Schmutzler RK, Wardley A, Mitchell G, Earl H, Wickens M, Carmichael J (2010) Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 376(9737):235-244. doi: 10.1016/S0140-6736(10) 60892-6
115. Veeriah S, Taylor BS, Meng S, Fang F, Yilmaz E, Vivanco I, Janakiraman M, Schultz N, Hanrahan AJ, Pao W, Ladanyi M, Sander C, Heguy A, Holland EC, Paty PB, Mischel PS, Liau L, Cloughesy TF, Mellinghoff IK, Solit DB, Chan TA (2010) Somatic mutations of the Parkinson's disease-associated gene PARK2 in glioblastoma and other human malignancies. Nat Genet 42(1):77-82. doi: 10.1038/ng.491
116. Wan XB, Fan XJ, Chen MY, Xiang J, Huang PY, Guo L, Wu XY, Xu J, Long ZJ, Zhao Y, Zhou WH, Mai HQ, Liu Q, Hong MH (2010) Elevated Beclin 1 expression is correlated with HIF-1alpha in predicting poor prognosis of nasopharyngeal carcinoma. Autophagy 6(3):395-404
117. Wang Y, Engels IH, Knee DA, Nasoff M, Deveraux QL, Quon KC (2004) Synthetic lethal targeting of MYC by activation of the DR5 death receptor pathway. Cancer Cell 5(5):501-512
118. Wei Y, Pattingre S, Sinha S, Bassik M, Levine B (2008) JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol Cell 30(6):678-688. doi: 10.1016/j.molcel.2008.06.001
119. White E (2012) Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer 12(6):401-410. doi: 10.1038/nrc3262
120. White E, Karp C, Strohecker AM, Guo Y, Mathew R (2010) Role of autophagy in suppression of inflammation and cancer. Curr Opin Cell Biol 22(2):212-217. doi: 10.1016/j.ceb.2009.12.008
121. Yang Z, Klionsky DJ (2010) Eaten alive: a history of macroautophagy. Nat Cell Biol 12(9):814-822. doi: 10.1038/ncb0910-814
122. Yang D, Liu H, Goga A, Kim S, Yuneva M, Bishop JM (2010) Therapeutic potential of a synthetic lethal interaction between the MYC proto-oncogene and inhibition of aurora-B kinase. Proc Natl Acad Sci USA 107(31):13836-13841. doi: 10.1073/pnas.1008366107
123. Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, Hoosen S, St Peter J, Haas T, Lebwohl D, Van Cutsem E, Kulke MH, Hobday TJ, O'Dorisio TM, Shah MH, Cadiot G, Luppi G, Posey JA, Wiedenmann B (2010) Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol 28(1):69-76. doi: 10.1200/JCO.2009.24.2669
124. Yla-Anttila P, Vihinen H, Jokitalo E, Eskelinen EL (2009) 3D tomography reveals connections between the phagophore and endoplasmic reticulum. Autophagy 5(8):1180-1185
125. Young AC, Craven RA, Cohen D, Taylor C, Booth C, Harnden P, Cairns DA, Astuti D, Gregory W, Maher ER, Knowles MA, Joyce A, Selby PJ, Banks RE (2009) Analysis of VHL gene alterations and their relationship to clinical parameters in sporadic conventional renal cell carcinoma. Clin Cancer Res Off J Am Assoc Cancer Res 15(24):7582-7592. doi: 10.1158/1078-0432. CCR-09-2131
126. Yu L, McPhee CK, Zheng L, Mardones GA, Rong Y, Peng J, Mi N, Zhao Y, Liu Z, Wan F, Hailey DW, Oorschot V, Klumperman J, Baehrecke EH, Lenardo MJ (2010) Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 465(7300):942-946. doi: 10.1038/nature09076
127. Yue Z, Jin S, Yang C, Levine AJ, Heintz N (2003) Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci USA 100(25):15077-15082. doi: 10.1073/pnas.2436255100
128. Zlatic SA, Tornieri K, L'Hernault SW, Faundez V (2011) Metazoan cell biology of the HOPS tethering complex. Cell Logist 1(3):111-117. doi: 10.4161/cl.1.3.17279
129. Zoncu R, Bar-Peled L, Efeyan A, Wang S, Sancak Y, Sabatini DM (2011) mTORC1 senses lyso-somal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase. Science 334(6056):678-683. doi: 10.1126/science.1207056