The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5

Journal of Clinical Investigation

Volumn 120, Issue 1, 2010, Pages 127-141

  Rouschop, Kasper M A ^a   Van Den Beucken, Twan ^a,b   Dubois, Ludwig ^a,c   Niessen, Hanneke ^a   Bussink, Johan ^d   Savelkouls, Kim ^a   Keulers, Tom ^a   Mujcic, Hilda ^a   Landuyt, Willy ^c   Voncken, Jan Willem ^a   Lambin, Philippe ^a   Van Der Kogel, Albert J ^d   Koritzinsky, Marianne ^a,b,e   Wouters, Bradly G ^a,b,e,f  

^a MAASTRICHT UNIVERSITY   (Netherlands)

^b PRINCESS MARGARET HOSPITAL   (Canada)

^c UNIVERSITY HOSPITALS LEUVEN   (Belgium)

^d RADBOUD UNIVERSITY MEDICAL CENTER   (Netherlands)

^e UNIVERSITY OF TORONTO   (Canada)

^f ONTARIO INSTITUTE FOR CANCER RESEARCH   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

ACTIVATING TRANSCRIPTION FACTOR 4; AUTOPHAGY RELATED GENE 5 PROTEIN; CELL PROTEIN; GROWTH ARREST AND DNA DAMAGE INDUCIBLE PROTEIN 153; INITIATION FACTOR; INITIATION FACTOR 2ALPHA; INITIATION FACTOR PERK; MICROTUBULE ASSOCIATED PROTEIN 1; MICROTUBULE ASSOCIATED PROTEIN 1 LIGHT CHAIN 3BETA; PROTEIN; UNCLASSIFIED DRUG; ATF4 PROTEIN, HUMAN; ATG5 PROTEIN, HUMAN; CHLOROQUINE; DDIT3 PROTEIN, HUMAN; MAP1LC3B PROTEIN, HUMAN; MESSENGER RNA; MICROTUBULE ASSOCIATED PROTEIN; PERK KINASE; PROTEIN KINASE R;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; AUTOPHAGOSOME; AUTOPHAGY; CANCER CELL CULTURE; CELL EXPANSION; CELL HYPOXIA; CELL PROTECTION; CELL SURVIVAL; CELL VIABILITY; CONTROLLED STUDY; FEMALE; HEAD AND NECK CARCINOMA; HUMAN; HUMAN CELL; IRRADIATION; MOUSE; NONHUMAN; PHAGOSOME; PRIORITY JOURNAL; PROTEIN DEPLETION; PROTEIN FOLDING; PROTEIN INDUCTION; SIGNAL TRANSDUCTION; SQUAMOUS CELL CARCINOMA; TRANSCRIPTION INITIATION; TRANSCRIPTION REGULATION; TUMOR CELL; TUMOR XENOGRAFT; ANIMAL; BAGG ALBINO MOUSE; GENETICS; METABOLISM; NEOPLASM; PHYSIOLOGY; TUMOR CELL LINE; UNFOLDED PROTEIN RESPONSE;

ACTIVATING TRANSCRIPTION FACTOR 4; ANIMALS; AUTOPHAGY; CELL HYPOXIA; CELL LINE, TUMOR; CHLOROQUINE; EIF-2 KINASE; FEMALE; HUMANS; MICE; MICE, INBRED BALB C; MICROTUBULE-ASSOCIATED PROTEINS; NEOPLASMS; RNA, MESSENGER; TRANSCRIPTION FACTOR CHOP; UNFOLDED PROTEIN RESPONSE;

EID: 74949118681     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI40027     Document Type: Article

References (76)

1. Dewhirst MW, Cao Y, Moeller B. Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat Rev Cancer. 2008;8(6):425-437.
2. Nordsmark M, et al. Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multicenter study. Radiother Oncol. 2005;77(1):18-24.
3. Brizel DM, Sibley GS, Prosnitz LR, Scher RL, Dewhirst MW. Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 1997;38(2):285-289.
4. Hockel M, Schlenger K, Aral B, Mitze M, Schaffer U, Vaupel P. Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res. 1996;56(19):4509-4515.
5. Young SD, Marshall RS, Hill RP. Hypoxia induces DNA overreplication and enhances metastatic potential of murine tumor cells. Proc Natl Acad Sci U S A. 1988;85(24):9533-9537.
6. Harris AL. Hypoxia--a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2(1):38-47.
7. Wouters BG, van den Beucken T, Magagnin MG, Lambin P, Koumenis C. Targeting hypoxia tolerance in cancer. Drug Resist Updat. 2004;7(1):25-40.
8. Graeber TG, et al. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature. 1996;379(6560):88-91.
9. Schofield CJ, Ratcliffe PJ. Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol. 2004;5(5):343-354.
10. Wouters BG, Koritzinsky M. Hypoxia signalling through mTOR and the unfolded protein response in cancer. Nat Rev Cancer. 2008;8(11):851-864.
11. Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol. 2007;8(7):519-529.
12. Vattem KM, Wek RC. Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. Proc Natl Acad Sci U S A. 2004;101(31):11269-11274.
13. Lu PD, Harding HP, Ron D. Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response. J Cell Biol. 2004;167(1):27-33.
14. Kojima E, et al. The function of GADD34 is a recovery from a shutoff of protein synthesis induced by ER stress: elucidation by GADD34-deficient mice. FASEB J. 2003;17(11):1573-1575.
15. Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell. 2001;107(7):881-891.
16. Ye J, et al. ER stress induces cleavage of membranebound ATF6 by the same proteases that process SREBPs. Mol Cell. 2000;6(6):1355-1364.
17. Koumenis C, et al. Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2alpha. Mol Cell Biol. 2002;22(21):7405-7416.
18. Koritzinsky M, et al. Phosphorylation of eIF2alpha is required for mRNA translation inhibition and survival during moderate hypoxia. Radiother Oncol. 2007;83(3):353-361.
19. Koritzinsky M, et al. Gene expression during acute and prolonged hypoxia is regulated by distinct mechanisms of translational control. EMBO J. 2006;25(5):1114-1125.
20. Blais JD, et al. Activating transcription factor 4 is translationally regulated by hypoxic stress. Mol Cell Biol. 2004;24(17):7469-7482.
21. Bi M, et al. ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. EMBO J. 2005;24(19):3470-3481.
22. Romero-Ramirez L, et al. XBP1 is essential for survival under hypoxic conditions and is required for tumor growth. Cancer Res. 2004;64(17):5943-5947.
23. Lin JH, et al. IRE1 signaling affects cell fate during the unfolded protein response. Science. 2007;318(5852):944-949.
24. Mizushima N. The pleiotropic role of autophagy: from protein metabolism to bactericide. Cell Death Differ. 2005;12(Suppl 2):1535-1541.
25. Zhang H, et al. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem. 2008;283(16):10892-10903.
26. Tanida I, Ueno T, Kominami E. LC3 conjugation system in mammalian autophagy. Int J Biochem Cell Biol. 2004;36(12):2503-2518.
27. Kuma A, et al. The role of autophagy during the early neonatal starvation period. Nature. 2004;432(7020):1032-1036.
28. Mizushima N, Ohsumi Y, Yoshimori T. Autophagosome formation in mammalian cells. Cell Struct Funct. 2002;27(6):421-429.
29. Ding WX, et al. Linking of autophagy to ubiquitinproteasome system is important for the regulation of endoplasmic reticulum stress and cell viability. Am J Pathol. 2007;171(2):513-524.
30. Iwata A, et al. Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation. Proc Natl Acad Sci U S A. 2005;102(37):13135-13140.
31. Tracy K, Dibling BC, Spike BT, Knabb JR, Schumacker P, Macleod KF. BNIP3 is an RB/E2F target gene required for hypoxia-induced autophagy. Mol Cell Biol. 2007;27(17):6229-6242.
32. Decker RS, Wildenthal K. Lysosomal alterations in hypoxic and reoxygenated hearts. I. Ultrastructural and cytochemical changes. Am J Pathol. 1980;98(2):425-444.
33. Papandreou I, Lim AL, Laderoute K, Denko NC. Hypoxia signals autophagy in tumor cells via AMPK activity, independent of HIF-1, BNIP3, and BNIP3L. Cell Death Differ. 2008;15(10):1572-1581.
34. Jin S, White E. Tumor suppression by autophagy through the management of metabolic stress. Autophagy. 2008;4(5):563-566.
35. Wijffels KI, et al. Patterns of proliferation related to vasculature in human head-and-neck carcinomas before and after transplantation in nude mice. Int J Radiat Oncol Biol Phys. 2001;51(5):1346-1353.
36. Kabeya Y, et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. Embo J. 2000;19(21):5720- 5728.
37. Boya P, et al. Inhibition of macroautophagy triggers apoptosis. Mol Cell Biol. 2005;25(3):1025-1040.
38. Yamamoto A, Tagawa Y, Yoshimori T, Moriyama Y, Masaki R, Tashiro Y. Bafilomycin A1 prevents maturation of autophagic vacuoles by inhibiting fusion between autophagosomes and lysosomes in rat hepatoma cell line, H-4-II-E cells. Cell Struct Funct. 1998;23(1):33-42.
39. Bacon AL, Fox S, Turley H, Harris AL. Selective silencing of the hypoxia-inducible factor 1 target gene BNIP3 by histone deacetylation and methylation in colorectal cancer. Oncogene. 2007;26(1):132-141.
40. Koritzinsky M, et al. The hypoxic proteome is influenced by gene-specific changes in mRNA translation. Radiother Oncol. 2005;76(2):177-186.
41. Novoa I, Zeng H, Harding HP, Ron D. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J Cell Biol. 2001;153(5):1011-1022.
42. Harding HP, et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell. 2000;6(5):1099-1108.
43. Milani M, et al. The role of ATF4 stabilization and autophagy in resistance of breast cancer cells treated with bortezomib. Cancer Res. 2009;69(10):4415-4423.
44. Papandreou I, Krishna C, Kaper F, Cai D, Giaccia AJ, Denko NC. Anoxia is necessary for tumor cell toxicity caused by a low-oxygen environment. Cancer Res. 2005;65(8):3171-3178.
45. Powers WE, Tolmach LJ. Demonstration of an anoxic component in a mouse tumor-cell population by in vivo assay of survival following irradiation. Radiology. 1964;83:328-336.
46. Maclean KH, Dorsey FC, Cleveland JL, Kastan MB. Targeting lysosomal degradation induces p53-dependent cell death and prevents cancer in mouse models of lymphomagenesis. J Clin Invest. 2008;118(1):79-88.
47. Bakkenist CJ, Kastan MB. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature. 2003;421(6922):499- 506.
48. Gomez-Manzano C, et al. Adenovirus-mediated transfer of the p53 gene produces rapid and generalized death of human glioma cells via apoptosis. Cancer Res. 1996;56(4):694-699.
49. Amaravadi RK, et al. Autophagy inhibition enhances therapy-induced apoptosis in a Mycinduced model of lymphoma. J Clin Invest. 2007;117(2):326-336.
50. Lum JJ, DeBerardinis RJ, Thompson CB. Autophagy in metazoans: cell survival in the land of plenty. Nat Rev Mol Cell Biol. 2005;6(6):439-448.
51. Marx J. Autophagy: is it cancer's friend or foe? Science. 2006;312(5777):1160-1161.
52. Jin S, White E. Role of autophagy in cancer: management of metabolic stress. Autophagy. 2007;3(1):28-31.
53. Klionsky DJ, Emr SD. Autophagy as a regulated pathway of cellular degradation. Science. 2000;290(5497):1717-1721.
54. Hara T, et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature. 2006;441(7095):885-889.
55. Komatsu M, et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature. 2006;441(7095):880-884.
56. Komatsu M, et al. Impairment of starvationinduced and constitutive autophagy in Atg7-deficient mice. J Cell Biol. 2005;169(3):425-434.
57. Pua HH, Dzhagalov I, Chuck M, Mizushima N, He YW. A critical role for the autophagy gene Atg5 in T cell survival and proliferation. J Exp Med. 2007;204(1):25-31.
58. Karantza-Wadsworth V, et al. Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev. 2007;21(13):1621-1635.
59. Mathew R, et al. Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev. 2007;21(11):1367-1381.
60. Kouroku Y, et al. ER stress (PERK/eIF2alpha phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation. Cell Death Differ. 2007;14(2):230-239.
61. Park MA, et al. Vorinostat and sorafenib increase ER stress, autophagy and apoptosis via ceramidedependent CD95 and PERK activation. Cancer Biol Ther. 2008;7(10):1648-1662.
62. Talloczy Z, et al. Regulation of starvation- and virus-induced autophagy by the eIF2alpha kinase signaling pathway. Proc Natl Acad Sci U S A. 2002;99(1):190-195.
63. Bernales S, McDonald KL, Walter P. Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol. 2006;4(12):e423.
64. Ogata M, et al. Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol. 2006;26(24):9220-9231.
65. Yorimitsu T, Klionsky DJ. Autophagy: molecular machinery for self-eating. Cell Death Differ. 2005;12(Suppl 2):1542-1552.
66. Mammucari C, et al. FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab. 2007;6(6):458-471.
67. Zhao J, et al. FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab. 2007;6(6):472-483.
68. Bakker WJ, Harris IS, Mak TW. FOXO3a is activated in response to hypoxic stress and inhibits HIF1-induced apoptosis via regulation of CITED2. Mol Cell. 2007;28(6):941-953.
69. Mizushima N, et al. Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. J Cell Biol. 2001;152(4):657-668.
70. Suzuki K, Kirisako T, Kamada Y, Mizushima N, Noda T, Ohsumi Y. The pre-autophagosomal structure organized by concerted functions of APG genes is essential for autophagosome formation. EMBO J. 2001;20(21):5971-5981.
71. Yousefi S, Simon HU. Apoptosis regulation by autophagy gene 5. Crit Rev Oncol Hematol. 2007;63(3):241-244.
72. Bellot G, et al. Hypoxia-induced autophagy is mediated through HIF-induction of BNIP3 and BNIP3L via their BH3-domains. Mol Cell Biol. 2009;29(10)):2570-2581.
73. Tajiri S, et al. Ischemia-induced neuronal cell death is mediated by the endoplasmic reticulum stress pathway involving CHOP. Cell Death Differ. 2004;11(4):403-415.
74. Oyadomari S, Mori M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ. 2004;11(4):381-389.
75. Rijken PF, Peters JP, Van der Kogel AJ. Quantitative analysis of varying profiles of hypoxia in relation to functional vessels in different human glioma xenograft lines. Radiat Res. 2002;157(6):626-632.
76. Bracken AP, et al. EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. EMBO J. 2003;22(20):5323-5335.