Autophagy: an adaptable modifier of tumourigenesis

Current Opinion in Genetics and Development

Volumn 20, Issue 1, 2010, Pages 57-64

  Wilkinson, Simon ^a   Ryan, Kevin M ^a  

^a BEATSON INSTITUTE FOR CANCER RESEARCH   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

PROTEIN; REACTIVE OXYGEN METABOLITE;

AUTOPHAGY; CANCER THERAPY; CARCINOGENESIS; CELL FUNCTION; CELL ORGANELLE; CELL VIABILITY; CYTOSOL; GENOMICS; HUMAN; IMMUNOGENICITY; INFLAMMATION; METABOLIC STRESS; MITOCHONDRION; ONCOGENE; PHENOTYPE; PRIORITY JOURNAL; PROTEIN QUALITY; REVIEW; SENESCENCE; SIGNAL TRANSDUCTION; TREATMENT RESPONSE; TUMOR CELL;

AUTOPHAGY; CELL DEATH; CELL SURVIVAL; HUMANS; INFLAMMATION; MITOCHONDRIA; NEOPLASMS; OXIDATIVE STRESS; REACTIVE OXYGEN SPECIES; SIGNAL TRANSDUCTION;

EID: 76149096897     PISSN: 0959437X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.gde.2009.12.004     Document Type: Review

References (55)

1. Lum J.J., DeBerardinis R.J., and Thompson C.B. Autophagy in metazoans: cell survival in the land of plenty. Nat Rev Mol Cell Biol 6 (2005) 439-448
2. Qu X., Yu J., Bhagat G., Furuya N., Hibshoosh H., Troxel A., Rosen J., Eskelinen E.L., Mizushima N., Ohsumi Y., et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest 112 (2003) 1809-1820
3. Ionov Y., Nowak N., Perucho M., Markowitz S., and Cowell J.K. Manipulation of nonsense mediated decay identifies gene mutations in colon cancer cells with microsatellite instability. Oncogene 23 (2004) 639-645
4. Jung H.S., Chung K.W., Won Kim J., Kim J., Komatsu M., Tanaka K., Nguyen Y.H., Kang T.M., Yoon K.H., Kim J.W., et al. Loss of autophagy diminishes pancreatic beta cell mass and function with resultant hyperglycemia. Cell Metab 8 (2008) 318-324
5. Yue Z., Jin S., Yang C., Levine A.J., and Heintz N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci U S A 100 (2003) 15077-15082
6. Takahashi Y., Coppola D., Matsushita N., Cualing H.D., Sun M., Sato Y., Liang C., Jung J.U., Cheng J.Q., Mule J.J., et al. Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat Cell Biol 9 (2007) 1142-1151
7. Marino G., Salvador-Montoliu N., Fueyo A., Knecht E., Mizushima N., and Lopez-Otin C. Tissue-specific autophagy alterations and increased tumorigenesis in mice deficient in Atg4C/autophagin-3. J Biol Chem 282 (2007) 18573-18583
8. •].
9. Hoyer-Hansen M., and Jaattela M. Autophagy: an emerging target for cancer therapy. Autophagy 4 (2008) 574-580
10. Degenhardt K., Mathew R., Beaudoin B., Bray K., Anderson D., Chen G., Mukherjee C., Shi Y., Gelinas C., Fan Y., et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 10 (2006) 51-64
11. Zhang H., Bosch-Marce M., Shimoda L.A., Tan Y.S., Baek J.H., Wesley J.B., Gonzalez F.J., and Semenza G.L. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem 283 (2008) 10892-10903
12. Wilkinson S., O'Prey J., Fricker M., and Ryan K.M. Hypoxia-selective macroautophagy and cell survival signaled by autocrine PDGFR activity. Genes Dev 23 (2009) 1283-1288
13. Ravikumar B., Berger Z., Vacher C., O'Kane C.J., and Rubinsztein D.C. Rapamycin pre-treatment protects against apoptosis. Hum Mol Genet 15 (2006) 1209-1216
14. Hoyer-Hansen M., and Jaattela M. Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium. Cell Death Differ 14 (2007) 1576-1582
15. •] this paper demonstrates the emerging concept that post-translational modification of would-be cargo proteins could be a point of regulation of autophagy. Specifically, acetylation of mutant huntingtin protein, the causative agent of Huntington's chorea, appears to permit the formation of autophagosomes that selectively degrade this species.
16. Ding W.X., Ni H.M., Gao W., Chen X., Kang J.H., Stolz D.B., Liu J., and Yin X.M. Oncogenic transformation confers a selective susceptibility to the combined suppression of the proteasome and autophagy. Mol Cancer Ther 8 (2009) 2036-2045
17. •].
18. ••].
19. Gamerdinger M., Hajieva P., Kaya A.M., Wolfrum U., Hartl F.U., and Behl C. Protein quality control during aging involves recruitment of the macroautophagy pathway by BAG3. EMBO J 28 (2009) 889-901
20. Kim P.K., Hailey D.W., Mullen R.T., and Lippincott-Schwartz J. Ubiquitin signals autophagic degradation of cytosolic proteins and peroxisomes. Proc Natl Acad Sci U S A 105 (2008) 20567-20574. This paper demonstrates that monoubiquitination or polyubiquitination is sufficient to target proteins and organelles to autophagosomes, suggesting that regulation of ubiquitination by ligases and deubiquitinases may be a point of signalling control for selective autophagy pathways.
21. •].
22. •] also demonstrates effectively that the phenotypic effects of inhibiting autophagy may be because of the consequent lack of sequestration of a target protein or adaptor. In this model, conditional knockout of the autophagy mediator Atg7 in the mouse liver leads to both nucleation of insoluble foci of ubiquitinated cytoplasmic protein species and hepatocyte abnormalities, dependent upon the presence of p62/SQSTM1.
23. •], this paper demonstrates that autophagy inhibition may have effects on cell function by compromise of turnover of a particular protein species. In this instance, p62/SQSTM1 accumulates in the cytosol when autophagy is inhibited. This is proposed to stabilise multiple ubiquitinated proteins, possibly via direct binding to p62 and sequestration from the proteasomal degradation pathway.
24. Jin Z., Li Y., Pitti R., Lawrence D., Pham V.C., Lill J.R., and Ashkenazi A. Cullin3-based polyubiquitination and p62-dependent aggregation of caspase-8 mediate extrinsic apoptosis signaling. Cell 137 (2009) 721-735
25. Galvez A.S., Duran A., Linares J.F., Pathrose P., Castilla E.A., Abu-Baker S., Leitges M., Diaz-Meco M.T., and Moscat J. Protein kinase Czeta represses the interleukin-6 promoter and impairs tumorigenesis in vivo. Mol Cell Biol 29 (2009) 104-115
26. ••] probable superaccumulation of p62/SQSTM1 inhibits NF-κB.
27. Young A.R., Narita M., Ferreira M., Kirschner K., Sadaie M., Darot J.F., Tavare S., Arakawa S., Shimizu S., Watt F.M., et al. Autophagy mediates the mitotic senescence transition. Genes Dev 23 (2009) 798-803. This paper is the first demonstration that oncogene-induced senescence can mechanistically involve the induction of autophagy, required for secretion of pro-senescence cytokines such as interleukin-6 and interleukin-8. Although most of the work was performed in fibroblasts and it remains to be shown that this functional role is conserved in nascent human neoplasia, the observation that senescent cells within nascent murine papillomas exhibit accumulated autophagosomes provides some tantalising evidence that this may be so.
28. Qu X., Zou Z., Sun Q., Luby-Phelps K., Cheng P., Hogan R.N., Gilpin C., and Levine B. Autophagy gene-dependent clearance of apoptotic cells during embryonic development. Cell 128 (2007) 931-946
29. Thorburn J., Horita H., Redzic J., Hansen K., Frankel A.E., and Thorburn A. Autophagy regulates selective HMGB1 release in tumor cells that are destined to die. Cell Death Differ 16 (2008) 175-183
30. Hashimoto D., Ohmuraya M., Hirota M., Yamamoto A., Suyama K., Ida S., Okumura Y., Takahashi E., Kido H., Araki K., et al. Involvement of autophagy in trypsinogen activation within the pancreatic acinar cells. J Cell Biol 181 (2008) 1065-1072. This study provides a convincing mechanistic description of one route by which autophagy may influence a pathologic state of organ inflammation that may promote tumourigenesis. In this model, acute pancreatic inflammation, which ultimately leads to chronic inflammation, is induced with endotoxic agents in mice. Autophagy is shown to be involved in the genesis of inflammation in response to the decapeptide cerulein, which stimulates digestive enzyme secretion. Specifically, autophagy mediates trypsin formation from trypsinogen proenzyme via transport of the latter to the lysosome in autophagosomes.
31. Saitoh T., Fujita N., Jang M.H., Uematsu S., Yang B.G., Satoh T., Omori H., Noda T., Yamamoto N., Komatsu M., et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature 456 (2008) 264-268
32. Cadwell K., Liu J.Y., Brown S.L., Miyoshi H., Loh J., Lennerz J.K., Kishi C., Kc W., Carrero J.A., Hunt S., et al. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 456 (2008) 259-263
33. Perlmutter D.H. Autophagic disposal of the aggregation-prone protein that causes liver inflammation and carcinogenesis in alpha-1-antitrypsin deficiency. Cell Death Differ 16 (2009) 39-45
34. Fortunato F., Burgers H., Bergmann F., Rieger P., Buchler M.W., Kroemer G., and Werner J. Impaired autolysosome formation correlates with Lamp-2 depletion: role of apoptosis, autophagy, and necrosis in pancreatitis. Gastroenterology 137 (2009) 350-360
35. Guertin D.A., and Sabatini D.M. Defining the role of mTOR in cancer. Cancer Cell 12 (2007) 9-22
36. Liu L., Cash T.P., Jones R.G., Keith B., Thompson C.B., and Simon M.C. Hypoxia-induced energy stress regulates mRNA translation and cell growth. Mol Cell 21 (2006) 521-531
37. Papandreou I., Lim A.L., Laderoute K., and Denko N.C. Hypoxia signals autophagy in tumor cells via AMPK activity, independent of HIF-1, BNIP3, and BNIP3L. Cell Death Differ 15 (2008) 1572-1581
38. Crighton D., Wilkinson S., O'Prey J., Syed N., Smith P., Harrison P.R., Gasco M., Garrone O., Crook T., and Ryan K.M. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 126 (2006) 121-134
39. Maiuri M.C., Malik S.A., Morselli E., Kepp O., Criollo A., Mouchel P.L., Carnuccio R., and Kroemer G. Stimulation of autophagy by the p53 target gene Sestrin2. Cell Cycle 8 (2009) 1571-1576
40. Budanov A.V., and Karin M. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 134 (2008) 451-460
41. Liang J., Shao S.H., Xu Z.X., Hennessy B., Ding Z., Larrea M., Kondo S., Dumont D.J., Gutterman J.U., Walker C.L., et al. The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis. Nat Cell Biol 9 (2007) 218-224
42. Zhao J., Brault J.J., Schild A., Cao P., Sandri M., Schiaffino S., Lecker S.H., and Goldberg A.L. FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab 6 (2007) 472-483
43. Mammucari C., Milan G., Romanello V., Masiero E., Rudolf R., Del Piccolo P., Burden S.J., Di Lisi R., Sandri C., Zhao J., et al. FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab 6 (2007) 458-471
44. Nicklin P., Bergman P., Zhang B., Triantafellow E., Wang H., Nyfeler B., Yang H., Hild M., Kung C., Wilson C., et al. Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136 (2009) 521-534
45. •] for annotation.
46. •], elevated levels of cytosolic p53 (wild-type or mutant) are shown to repress autophagy, predominantly the degradation of ER fragments (reticulophagy) but also possibly some mitophagy. As mutants of p53 are capable of performing this function, and as some p53 mutants are hyperstabilised and accumulate in the cytosol, this then raises the tantalising possibility that the inhibition of autophagy by some mutant forms of p53 may be a component of their gain-of-function activity.
47. •].
48. Maiuri M.C., Le Toumelin G., Criollo A., Rain J.C., Gautier F., Juin P., Tasdemir E., Pierron G., Troulinaki K., Tavernarakis N., et al. Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1. EMBO J 26 (2007) 2527-2539
49. Wei Y., Pattingre S., Sinha S., Bassik M., and Levine B. JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol Cell 30 (2008) 678-688
50. Scherz-Shouval R., Shvets E., Fass E., Shorer H., Gil L., and Elazar Z. Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J 26 (2007) 1749-1760
51. Reef S., Zalckvar E., Shifman O., Bialik S., Sabanay H., Oren M., and Kimchi A. A short mitochondrial form of p19(ARF) induces autophagy and caspase-independent cell death. Mol Cell 22 (2006) 463-475
52. Pimkina J., Humbey O., Zilfou J.T., Jarnik M., and Murphy M. ARF induces autophagy by virtue of interaction with Bcl-xl. J Biol Chem 284 (2008) 2803-2810
53. Bains M., Florez-McClure M.L., and Heidenreich K.A. Insulin-like growth factor-I prevents the accumulation of autophagic vesicles and cell death in Purkinje neurons by increasing the rate of autophagosome-to-lysosome fusion and degradation. J Biol Chem 284 (2009) 20398-20407
54. •] for annotation.
55. •] demonstrates that hydroxychloroquine can enhance the activity of the Bcr-Abl fusion tyrosine kinase inhibitor imatinib in killing of chronic myeloid leukaemia (CML) cells in a mouse model where the cancer is driven by the Bcr-Abl fusion kinase, as well as in patient-derived samples in vitro. The effectiveness of this as a therapy is also demonstrated in vitro in the toxicity of this combination against otherwise refractory CML stem cells. Furthermore, targeting autophagy along with imatinib treatment is only effective against cells bearing the Bcr-Abl fusion, giving confidence in the ability of this combination to selectively kill cancer cells.