REVIEW

Autophagy in cancer biology and therapy

  • Noor GAMMOH ,
  • Simon WILKINSON
Expand
  • Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, United Kingdom, EH4 2XR

Received date: 13 Nov 2013

Accepted date: 04 Jan 2014

Published date: 01 Feb 2014

Copyright

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg

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.

Cite this article

Noor GAMMOH , Simon WILKINSON . Autophagy in cancer biology and therapy[J]. Frontiers in Biology, 2014 , 9(1) : 35 -50 . DOI: 10.1007/s11515-014-1294-2

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

Outlines

/