Autophagy in cancer biology and therapy

Abstract

The role of macroautophagy (hereafter autophagy) in cancer biology and response to clinical intervention is complex. It is clear that autophagy is dysregulated in a wide variety of tumor settings, both during tumor initiation and progression, and in response to therapy. However, the pleiotropic mechanistic roles of autophagy in controlling cell behavior make it difficult to predict in a given tumor setting what the role of autophagy, and, by extension, the therapeutic outcome of targeting autophagy, might be. In this review we summarize the evidence in the literature supporting pro- and anti-tumorigenic and-therapeutic roles of autophagy in cancer. This overview encompasses roles of autophagy in nutrient management, cell death, cell senescence, regulation of proteotoxic stress and cellular homeostasis, regulation of tumor-host interactions and participation in changes in metabolism. We also try to understand, where possible, the mechanistic bases of these roles for autophagy. We specifically expand on the emerging role of genetically-engineered mouse models of cancer in shedding light on these issues in vivo. We also consider how any or all of the above functions of autophagy proteins might be targetable by extant or future classes of pharmacologic agents. We conclude by briefly exploring non-canonical roles for subsets of the key autophagy proteins in cellular processes, and how these might impact upon cancer.

Keywords

autophagy / cancer / inflammation / metabolism / apoptosis / homeostasis

References

[1] Barré B, Perkins N D (2010). The Skp2 promoter integrates signaling through the NF-κB, p53, and Akt/GSK3β pathways to regulate autophagy and apoptosis. Mol Cell, 38(4): 524–538

[2] Behrends C, Sowa M E, Gygi S P, Harper J W (2010). Network organization of the human autophagy system. Nature, 466(7302): 68–76

[3] Bellodi C, Lidonnici M R, Hamilton A, Helgason G V, Soliera A R, Ronchetti M, Galavotti S, Young K W, Selmi T, Yacobi R, Van Etten R A, Donato N, Hunter A, Dinsdale D, Tirrò E, Vigneri P, Nicotera P, Dyer M J, Holyoake T, Salomoni P, Calabretta B (2009). Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells. J Clin Invest, 119(5): 1109–1123

[4] Bensaad K, Cheung E C, Vousden K H (2009). Modulation of intracellular ROS levels by TIGAR controls autophagy. EMBO J, 28(19): 3015–3026

[5] Bjørkøy G, Lamark T, Brech A, Outzen H, Perander M, Overvatn A, Stenmark H, Johansen T (2005). p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol, 171(4): 603–614

[6] Boya P, González-Polo R A, Casares N, Perfettini J L, Dessen P, Larochette N, Métivier D, Meley D, Souquere S, Yoshimori T, Pierron G, Codogno P, Kroemer G (2005). Inhibition of macroautophagy triggers apoptosis. Mol Cell Biol, 25(3): 1025–1040

[7] Capparelli C, Guido C, Whitaker-Menezes D, Bonuccelli G, Balliet R, Pestell T G, Goldberg A F, Pestell R G, Howell A, Sneddon S, Birbe R, Tsirigos A, Martinez-Outschoorn U, Sotgia F, Lisanti M P (2012). Autophagy and senescence in cancer-associated fibroblasts metabolically supports tumor growth and metastasis via glycolysis and ketone production. Cell Cycle, 11(12): 2285–2302

[8] Cesari R, Martin E S, Calin G A, Pentimalli F, Bichi R, McAdams H, Trapasso F, Drusco A, Shimizu M, Masciullo V, D’Andrilli G, Scambia G, Picchio M C, Alder H, Godwin A K, Croce C M (2003). 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(10): 5956–5961

[9] Chang T K, Shravage B V, Hayes S D, Powers C M, Simin R T, Wade Harper J, Baehrecke E H (2013). Uba1 functions in Atg7- and Atg3-independent autophagy. Nat Cell Biol, 15(9): 1067–1078

[10] Cheong H, Lindsten T, Wu J, Lu C, Thompson C B (2011). Ammonia-induced autophagy is independent of ULK1/ULK2 kinases. Proc Natl Acad Sci USA, 108(27): 11121–11126

[11] Cheong H, Wu J, Gonzales L K, Guttentag S H, Thompson C B, Lindsten T (2014). Analysis of a lung defect in autophagy-deficient mouse strains. Autophagy, 10(1): 45–56

[12] Ciechanover A (2005). Proteolysis: from the lysosome to ubiquitin and the proteasome. Nat Rev Mol Cell Biol, 6(1): 79–87

[13] Colleran A, Ryan A, O’Gorman A, Mureau C, Liptrot C, Dockery P, Fearnhead H, Egan L J (2011). Autophagosomal IkappaB alpha degradation plays a role in the long term control of tumor necrosis factor-alpha-induced nuclear factor-kappaB (NF-κB) activity. J Biol Chem, 286(26): 22886–22893

[14] Crighton D, Wilkinson S, O’Prey J, Syed N, Smith P, Harrison P R, Gasco M, Garrone O, Crook T, Ryan K M (2006). DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell, 126(1): 121–134

[15] Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, Mukherjee C, Shi Y, Gélinas C, Fan Y, Nelson D A, Jin S, White E (2006). Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell, 10(1): 51–64

[16] Deretic V, Saitoh T, Akira S (2013). Autophagy in infection, inflammation and immunity. Nat Rev Immunol, 13(10): 722–737

[17] Di Bartolomeo S, Corazzari M, Nazio F, Oliverio S, Lisi G, Antonioli M, Pagliarini V, Matteoni S, Fuoco C, Giunta L, D’Amelio M, Nardacci R, Romagnoli A, Piacentini M, Cecconi F, Fimia G M (2010). The dynamic interaction of AMBRA1 with the dynein motor complex regulates mammalian autophagy. J Cell Biol, 191(1): 155–168

[18] Djavaheri-Mergny M, Amelotti M, Mathieu J, Besançon F, Bauvy C, Souquère S, Pierron G, Codogno P (2006). NF-κB activation represses tumor necrosis factor-α-induced autophagy. J Biol Chem, 281(41): 30373–30382

[19] Dörr J R, Yu Y, Milanovic M, Beuster G, Zasada C, Däbritz J H, Lisec J, Lenze D, Gerhardt A, Schleicher K, Kratzat S, Purfürst B, Walenta S, Mueller-Klieser W, Gräler M, Hummel M, Keller U, Buck A K, Dörken B, Willmitzer L, Reimann M, Kempa S, Lee S, Schmitt C A (2013). Synthetic lethal metabolic targeting of cellular senescence in cancer therapy. Nature, 501(7467): 421–425

[20] Dupont N, Jiang S, Pilli M, Ornatowski W, Bhattacharya D, Deretic V (2011). Autophagy-based unconventional secretory pathway for extracellular delivery of IL-1β. EMBO J, 30(23): 4701–4711

[21] Duran A, Amanchy R, Linares J F, Joshi J, Abu-Baker S, Porollo A, Hansen M, Moscat J, Diaz-Meco M T (2011). p62 is a key regulator of nutrient sensing in the mTORC1 pathway. Mol Cell, 44(1): 134–146

[22] Elgendy M, Sheridan C, Brumatti G, Martin S J (2011). Oncogenic Ras-induced expression of Noxa and Beclin-1 promotes autophagic cell death and limits clonogenic survival. Mol Cell, 42(1): 23–35

[23] Fliss P M, Jowers T P, Brinkmann M M, Holstermann B, Mack C, Dickinson P, Hohenberg H, Ghazal P, Brune W (2012). Viral mediated redirection of NEMO/IKKγ to autophagosomes curtails the inflammatory cascade. PLoS Pathog, 8(2): e1002517

[24] Gammoh N, Florey O, Overholtzer M, Jiang X (2013). Interaction between FIP200 and ATG16L1 distinguishes ULK1 complex-dependent and-independent autophagy. Nat Struct Mol Biol, 20(2): 144–149

[25] Ganley I G, Lam H, Wang J, Ding X, Chen S, Jiang X (2009). ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem, 284(18): 12297–12305

[26] Gao C, Cao W, Bao L, Zuo W, Xie G, Cai T, Fu W, Zhang J, Wu W, Zhang X, Chen Y G (2010a). Autophagy negatively regulates Wnt signalling by promoting Dishevelled degradation. Nat Cell Biol, 12(8): 781–790

[27] Gao Z, Gammoh N, Wong P M, Erdjument-Bromage H, Tempst P, Jiang X (2010b). Processing of autophagic protein LC3 by the 20S proteasome. Autophagy, 6(1): 126–137

[28] Garg A D, Dudek A M, Ferreira G B, Verfaillie T, Vandenabeele P, Krysko D V, Mathieu C, Agostinis P (2013). ROS-induced autophagy in cancer cells assists in evasion from determinants of immunogenic cell death. Autophagy, 9(9): 1292–1307

[29] Geng J, Klionsky D J (2008). The Atg8 and Atg12 ubiquitin-like conjugation systems in macroautophagy. ‘Protein modifications: beyond the usual suspects’ review series. EMBO Rep, 9(9): 859–864

[30] Goussetis D J, Gounaris E, Wu E J, Vakana E, Sharma B, Bogyo M, Altman J K, Platanias L C (2012). Autophagic degradation of the BCR-ABL oncoprotein and generation of antileukemic responses by arsenic trioxide. Blood, 120(17): 3555–3562

[31] Grivennikov S I, Greten F R, Karin M (2010). Immunity, inflammation, and cancer. Cell, 140(6): 883–899

[32] Guo J Y, Chen H Y, Mathew R, Fan J, Strohecker A M, Karsli-Uzunbas G, Kamphorst J J, Chen G, Lemons J M, Karantza V, Coller H A, Dipaola R S, Gelinas C, Rabinowitz J D, White E (2011). Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev, 25(5): 460–470

[33] Guo J Y, Karsli-Uzunbas G, Mathew R, Aisner S C, Kamphorst J J, Strohecker A M, Chen G, Price S, Lu W, Teng X, Snyder E, Santanam U, Dipaola R S, Jacks T, Rabinowitz J D, White E (2013). Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis. Genes Dev, 27(13): 1447–1461

[34] He C, Wei Y, Sun K, Li B, Dong X, Zou Z, Liu Y, Kinch L N, Khan S, Sinha S, Xavier R J, Grishin N V, Xiao G, Eskelinen E L, Scherer P E, Whistler J L, Levine B (2013). Beclin 2 functions in autophagy, degradation of G protein-coupled receptors, and metabolism. Cell, 154(5): 1085–1099

[35] Inami Y, Waguri S, Sakamoto A, Kouno T, Nakada K, Hino O, Watanabe S, Ando J, Iwadate M, Yamamoto M, Lee M S, Tanaka K, Komatsu M (2011). Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells. J Cell Biol, 193(2): 275–284

[36] Isakson P, Bjørås M, Bøe S O, Simonsen A (2010). Autophagy contributes to therapy-induced degradation of the PML/RARA oncoprotein. Blood, 116(13): 2324–2331

[37] Jia L, Gopinathan G, Sukumar J T, Gribben J G (2012). Blocking autophagy prevents bortezomib-induced NF-κB activation by reducing I-κBα degradation in lymphoma cells. PLoS ONE, 7(2): e32584

[38] Jin S M, Youle R J (2012). PINK1- and Parkin-mediated mitophagy at a glance. J Cell Sci, 125(Pt 4): 795–799

[39] Johansen T, Lamark T (2011). Selective autophagy mediated by autophagic adapter proteins. Autophagy, 7(3): 279–296

[40] Jung C H, Jun C B, Ro S H, Kim Y M, Otto N M, Cao J, Kundu M, Kim D H (2009). ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell, 20(7): 1992–2003

[41] Karantza-Wadsworth V, Patel S, Kravchuk O, Chen G, Mathew R, Jin S, White E (2007). Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev, 21(13): 1621–1635

[42] Kenzelmann Broz D, Spano Mello S, Bieging K T, Jiang D, Dusek R L, Brady C A, Sidow A, Attardi L D (2013). Global genomic profiling reveals an extensive p53-regulated autophagy program contributing to key p53 responses. Genes Dev, 27(9): 1016–1031

[43] Kim J, Kim Y C, Fang C, Russell R C, Kim J H, Fan W, Liu R, Zhong Q, Guan K L (2013a). Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy. Cell, 152(1–2): 290–303

[44] Kim J, Kundu M, Viollet B, Guan K L (2011a). AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol, 13(2): 132–141

[45] Kim K W, Paul P, Qiao J, Chung D H (2013b). Autophagy mediates paracrine regulation of vascular endothelial cells. Lab Invest, 93(6): 639–645

[46] Kim M J, Woo S J, Yoon C H, Lee J S, An S, Choi Y H, Hwang S G, Yoon G, Lee S J (2011b). Involvement of autophagy in oncogenic K-Ras-induced malignant cell transformation. J Biol Chem, 286(15): 12924–12932

[47] Komatsu M, Kurokawa H, Waguri S, Taguchi K, Kobayashi A, Ichimura Y, Sou Y S, Ueno I, Sakamoto A, Tong K I, Kim M, Nishito Y, Iemura S, Natsume T, Ueno T, Kominami E, Motohashi H, Tanaka K, Yamamoto M (2010). The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol, 12(3): 213–223

[48] Komatsu M, Waguri S, Ueno T, Iwata J, Murata S, Tanida I, Ezaki J, Mizushima N, Ohsumi Y, Uchiyama Y, Kominami E, Tanaka K, Chiba T (2005). Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol, 169(3): 425–434

[49] Kon M, Kiffin R, Koga H, Chapochnick J, Macian F, Varticovski L, Cuervo A M (2011). Chaperone-mediated autophagy is required for tumor growth. Sci Transl Med, 3: 109ra117

[50] Kraft C, Peter M, Hofmann K (2010). Selective autophagy: ubiquitin-mediated recognition and beyond. Nat Cell Biol, 12(9): 836–841

[51] Kuballa P, Nolte W M, Castoreno A B, Xavier R J (2012). Autophagy and the immune system. Annu Rev Immunol, 30(1): 611–646

[52] Kuo T C, Chen C T, Baron D, Onder T T, Loewer S, Almeida S, Weismann C M, Xu P, Houghton J M, Gao F B, Daley G Q, Doxsey S (2011). Midbody accumulation through evasion of autophagy contributes to cellular reprogramming and tumorigenicity. Nat Cell Biol, 13(10): 1214–1223

[53] Lau A, Zheng Y, Tao S, Wang H, Whitman S A, White E, Zhang D D (2013). Arsenic inhibits autophagic flux, activating the Nrf2-Keap1 pathway in a p62-dependent manner. Mol Cell Biol, 33(12): 2436–2446

[54] Lee E J, Tournier C (2011). The requirement of uncoordinated 51-like kinase 1 (ULK1) and ULK2 in the regulation of autophagy. Autophagy, 7(7): 689–695

[55] Lee I H, Kawai Y, Fergusson M M, Rovira I I, Bishop A J, Motoyama N, Cao L, Finkel T (2012). Atg7 modulates p53 activity to regulate cell cycle and survival during metabolic stress. Science, 336(6078): 225–228

[56] Lee S J, Kim H P, Jin Y, Choi A M, Ryter S W (2011). Beclin 1 deficiency is associated with increased hypoxia-induced angiogenesis. Autophagy, 7(8): 829–839

[57] Levine B, Mizushima N, Virgin H W (2011). Autophagy in immunity and inflammation. Nature, 469(7330): 323–335

[58] Liu H, He Z, von Rutte T, Yousefi S, Hunger R E, Simon H U (2013). Down-Regulation of Autophagy-Related Protein 5 (ATG5) Contributes to the Pathogenesis of Early-Stage Cutaneous Melanoma. Sci Transl Med, 5: 202ra123

[59] Lock R, Roy S, Kenific C M, Su J S, Salas E, Ronen S M, Debnath J (2011). Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation. Mol Biol Cell, 22(2): 165–178

[60] Lu Z, Luo R Z, Lu Y, Zhang X, Yu Q, Khare S, Kondo S, Kondo Y, Yu Y, Mills G B, Liao W S, Bast R C Jr (2008). The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human ovarian cancer cells. J Clin Invest, 118(12): 3917–3929

[61] Lum J J, Bauer D E, Kong M, Harris M H, Li C, Lindsten T, Thompson C B (2005). Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell, 120(2): 237–248

[62] Maes H, Rubio N, Garg A D, Agostinis P (2013). Autophagy: shaping the tumor microenvironment and therapeutic response. Trends Mol Med, 19(7): 428–446

[63] Maskey D, Yousefi S, Schmid I, Zlobec I, Perren A, Friis R, Simon H U (2013). ATG5 is induced by DNA-damaging agents and promotes mitotic catastrophe independent of autophagy. Nature Commun, 4: 2130

[64] Mathew R, Karp C M, Beaudoin B, Vuong N, Chen G, Chen H Y, Bray K, Reddy A, Bhanot G, Gelinas C, Dipaola R S, Karantza-Wadsworth V, White E (2009). Autophagy suppresses tumorigenesis through elimination of p62. Cell, 137(6): 1062–1075

[65] Mathew R, Kongara S, Beaudoin B, Karp C M, 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

[66] 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(2): 200–212

[67] Michaud M, Martins I, Sukkurwala A Q, Adjemian S, Ma Y, Pellegatti P, Shen S, Kepp O, Scoazec M, Mignot G, Rello-Varona S, Tailler M, Menger L, Vacchelli E, Galluzzi L, Ghiringhelli F, di Virgilio F, Zitvogel L, Kroemer G (2011). Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science, 334(6062): 1573–1577

[68] Mizushima N, Komatsu M (2011). Autophagy: renovation of cells and tissues. Cell, 147(4): 728–741

[69] Mizushima N, Yamamoto A, Hatano M, Kobayashi Y, Kabeya Y, Suzuki K, Tokuhisa T, Ohsumi Y, Yoshimori T (2001). Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. J Cell Biol, 152(4): 657–668

[70] Mortensen M, Soilleux E J, Djordjevic G, Tripp R, Lutteropp M, Sadighi-Akha E, Stranks A J, Glanville J, Knight S, Jacobsen S E, Kranc K R, Simon A K (2011). The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance. J Exp Med, 208(3): 455–467

[71] Musiwaro P, Smith M, Manifava M, Walker S A, Ktistakis N T (2013). Characteristics and requirements of basal autophagy in HEK 293 cells. Autophagy, 9(9): 1407–1417

[72] Narita M, Young A R, Arakawa S, Samarajiwa S A, Nakashima T, Yoshida S, Hong S, Berry L S, Reichelt S, Ferreira M, Tavaré S, Inoki K, Shimizu S, Narita M (2011). Spatial coupling of mTOR and autophagy augments secretory phenotypes. Science, 332(6032): 966–970

[73] Newman A C, Scholefield C L, Kemp A J, Newman M, McIver E G, Kamal A, Wilkinson S (2012). TBK1 kinase addiction in lung cancer cells is mediated via autophagy of Tax1bp1/Ndp52 and non-canonical NF-κB signalling. PLoS ONE, 7(11): e50672

[74] Noman M Z, Janji B, Kaminska B, Van Moer K, Pierson S, Przanowski P, Buart S, Berchem G, Romero P, Mami-Chouaib F, Chouaib S (2011). Blocking hypoxia-induced autophagy in tumors restores cytotoxic T-cell activity and promotes regression. Cancer Res, 71(18): 5976–5986

[75] Paul S, Kashyap A K, Jia W, He Y W, Schaefer B C (2012). Selective autophagy of the adaptor protein Bcl10 modulates T cell receptor activation of NF-κB. Immunity, 36(6): 947–958

[76] Penna F, Costamagna D, Pin F, Camperi A, Fanzani A, Chiarpotto E M, Cavallini G, Bonelli G, Baccino F M, Costelli P (2013). Autophagic degradation contributes to muscle wasting in cancer cachexia. Am J Pathol, 182(4): 1367–1378

[77] Petherick K J, Williams A C, Lane J D, Ordóñez-Morán P, Huelsken J, Collard T J, Smartt H J, Batson J, Malik K, Paraskeva C, Greenhough A (2013). Autolysosomal β-catenin degradation regulates Wnt-autophagy-p62 crosstalk. EMBO J, 32(13): 1903–1916

[78] Pohl C, Jentsch S (2009). Midbody ring disposal by autophagy is a post-abscission event of cytokinesis. Nat Cell Biol, 11(1): 65–70

[79] Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, Rosen J, Eskelinen E L, 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

[80] Radoshevich L, Murrow L, Chen N, Fernandez E, Roy S, Fung C, Debnath J (2010). ATG12 conjugation to ATG3 regulates mitochondrial homeostasis and cell death. Cell, 142(4): 590–600

[81] Reggiori F, Komatsu M, Finley K, Simonsen A (2012). Autophagy: more than a nonselective pathway. Int J Cell Biol, 2012: 219625

[82] Rosenfeldt M T, O’Prey J, Morton J P, Nixon C, MacKay G, Mrowinska A, Au A, Rai T S, Zheng L, Ridgway R, Adams P D, Anderson K I, Gottlieb E, Sansom O J, Ryan K M (2013). p53 status determines the role of autophagy in pancreatic tumour development. Nature, 504(7479): 296–300

[83] 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. Mol Cell, 44(5): 698–709

[84] Rubinsztein D C, Shpilka T, Elazar Z (2012). Mechanisms of autophagosome biogenesis. Curr Biol, 22(1): R29–R34

[85] Russell R C, Tian Y, Yuan H, Park H W, Chang Y Y, Kim J, Kim H, Neufeld T P, Dillin A, Guan K L (2013). ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nat Cell Biol, 15(7): 741–750

[86] Saitoh T, Fujita N, Jang M H, Uematsu S, Yang B G, Satoh T, Omori H, Noda T, Yamamoto N, Komatsu M, Tanaka K, Kawai T, Tsujimura T, Takeuchi O, Yoshimori T, Akira S (2008). Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature, 456(7219): 264–268

[87] Sandilands E, Serrels B, McEwan D G, Morton J P, Macagno J P, McLeod K, Stevens C, Brunton V G, Langdon W Y, Vidal M, Sansom O J, Dikic I, Wilkinson S, Frame M C (2012a). Autophagic targeting of Src promotes cancer cell survival following reduced FAK signalling. Nat Cell Biol, 14(1): 51–60

[88] Sandilands E, Serrels B, Wilkinson S, Frame M C (2012b). Src-dependent autophagic degradation of Ret in FAK-signalling-defective cancer cells. EMBO Rep, 13(8): 733–740

[89] Shang L, Wang X (2011). AMPK and mTOR coordinate the regulation of Ulk1 and mammalian autophagy initiation. Autophagy, 7(8): 924–926

[90] Sheen J H, Zoncu R, Kim D, Sabatini D M (2011). Defective regulation of autophagy upon leucine deprivation reveals a targetable liability of human melanoma cells in vitro and in vivo. Cancer Cell, 19(5): 613–628

[91] Shibata T, Ohta T, Tong K I, Kokubu A, Odogawa R, Tsuta K, Asamura H, Yamamoto M, Hirohashi S (2008). Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Proc Natl Acad Sci USA, 105(36): 13568–13573

[92] Shimizu S, Kanaseki T, Mizushima N, Mizuta T, Arakawa-Kobayashi S, Thompson C B, Tsujimoto Y (2004). Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nat Cell Biol, 6(12): 1221–1228

[93] Shoji-Kawata S, Sumpter R, Leveno M, Campbell G R, Zou Z, Kinch L, Wilkins A D, Sun Q, Pallauf K, MacDuff D, Huerta C, Virgin H W, Helms J B, Eerland R, Tooze S A, Xavier R, Lenschow D J, Yamamoto A, King D, Lichtarge O, Grishin N V, Spector S A, Kaloyanova D V, Levine B (2013). Identification of a candidate therapeutic autophagy-inducing peptide. Nature, 494(7436): 201–206

[94] Stingele S, Stoehr G, Peplowska K, Cox J, Mann M, Storchova Z (2012). Global analysis of genome, transcriptome and proteome reveals the response to aneuploidy in human cells. Mol Syst Biol, 8: 608

[95] Strohecker A M, Guo J Y, Karsli-Uzunbas G, Price S M, Chen G J, Mathew R, McMahon M, White E (2013). Autophagy sustains mitochondrial glutamine metabolism and growth of BRAFV600E-driven lung tumors. Cancer Discov. doi: 10.1158/2159-8290.CD-13-0397

[96] Sui X, Chen R, Wang Z, Huang Z, Kong N, Zhang M, Han W, Lou F, Yang J, Zhang Q, Wang X, He C, Pan H (2013). Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment. Cell Death Dis, 4(10): e838

[97] 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

[98] Tang Y C, Williams B R, Siegel J J, Amon A (2011). Identification of aneuploidy-selective antiproliferation compounds. Cell, 144(4): 499–512

[99] Wang R C, Wei Y, An Z, Zou Z, Xiao G, Bhagat G, White M, Reichelt J, Levine B (2012a). Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation. Science, 338(6109): 956–959

[100] Wang Y, Wang X D, Lapi E, Sullivan A, Jia W, He Y W, Ratnayaka I, Zhong S, Goldin R D, Goemans C G, Tolkovsky A M, Lu X (2012b). Autophagic activity dictates the cellular response to oncogenic RAS. Proc Natl Acad Sci USA, 109(33): 13325–13330

[101] Wei H, Wei S, Gan B, Peng X, Zou W, Guan J L (2011). Suppression of autophagy by FIP200 deletion inhibits mammary tumorigenesis. Genes Dev, 25(14): 1510–1527

[102] Wei Y, Zou Z, Becker N, Anderson M, Sumpter R, Xiao G, Kinch L, Koduru P, Christudass C S, Veltri R W, Grishin N V, Peyton M, Minna J, Bhagat G, Levine B (2013). EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance. Cell, 154(6): 1269–1284

[103] Weidberg H, Shpilka T, Shvets E, Abada A, Shimron F, Elazar Z (2011). LC3 and GATE-16 N termini mediate membrane fusion processes required for autophagosome biogenesis. Dev Cell, 20(4): 444–454

[104] Wild P, Farhan H, McEwan D G, Wagner S, Rogov V V, Brady N R, Richter B, Korac J, Waidmann O, Choudhary C, Dötsch V, Bumann D, Dikic I (2011). Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science, 333(6039): 228–233

[105] Wilkinson S, O’Prey J, Fricker M, Ryan K M (2009). Hypoxia-selective macroautophagy and cell survival signaled by autocrine PDGFR activity. Genes Dev, 23(11): 1283–1288

[106] Wirawan E, Vanden Berghe T, Lippens S, Agostinis P, Vandenabeele P (2012). Autophagy: for better or for worse. Cell Res, 22(1): 43–61

[107] Wong P M, Puente C, Ganley I G, Jiang X (2013). The ULK1 complex: sensing nutrient signals for autophagy activation. Autophagy, 9(2): 124–137

[108] Xie Z, Klionsky D J (2007). Autophagosome formation: core machinery and adaptations. Nat Cell Biol, 9(10): 1102–1109

[109] Yang S, Wang X, Contino G, Liesa M, Sahin E, Ying H, Bause A, Li Y, Stommel J M, Dell’antonio G, Mautner J, Tonon G, Haigis M, Shirihai O S, Doglioni C, Bardeesy N, Kimmelman A C (2011). Pancreatic cancers require autophagy for tumor growth. Genes Dev, 25(7): 717–729

[110] Yee K S, Wilkinson S, James J, Ryan K M, Vousden K H (2009). PUMA- and Bax-induced autophagy contributes to apoptosis. Cell Death Differ, 16(8): 1135–1145

[111] Young A R, Narita M, Ferreira M, Kirschner K, Sadaie M, Darot J F, Tavaré S, Arakawa S, Shimizu S, Watt F M, Narita M (2009). Autophagy mediates the mitotic senescence transition. Genes Dev, 23(7): 798–803

[112] Yousefi S, Perozzo R, Schmid I, Ziemiecki A, Schaffner T, Scapozza L, Brunner T, Simon H U (2006). Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nat Cell Biol, 8(10): 1124–1132

[113] Yu L, Alva A, Su H, Dutt P, Freundt E, Welsh S, Baehrecke E H, Lenardo M J (2004). Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science, 304(5676): 1500–1502

[114] Yu L, Wan F, Dutta S, Welsh S, Liu Z, Freundt E, Baehrecke E H, Lenardo M (2006). Autophagic programmed cell death by selective catalase degradation. Proc Natl Acad Sci USA, 103(13): 4952–4957

[115] 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. Proc Natl Acad Sci USA, 100(25): 15077–15082

[116] Zhao Y, Yang J, Liao W, Liu X, Zhang H, Wang S, Wang D, Feng J, Yu L, Zhu W G (2010). Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity. Nat Cell Biol, 12(7): 665–675

RIGHTS & PERMISSIONS

Higher Education Press and Springer-Verlag Berlin Heidelberg