Hypoxia signalling through mTOR and the unfolded protein response in cancer

Nature Reviews Cancer

Volumn 8, Issue 11, 2008, Pages 851-864

  Wouters, Bradly G ^a,b,c,d   Koritzinsky, Marianne ^a,b,d  

^a PRINCESS MARGARET HOSPITAL   (Canada)

^b UNIVERSITY OF TORONTO   (Canada)

^c ONTARIO INSTITUTE FOR CANCER RESEARCH   (Canada)

^d MAASTRICHT UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

BORTEZOMIB; CETUXIMAB; GEFITINIB; GELDANAMYCIN; HYPOXIA INDUCIBLE FACTOR 1; IMATINIB; MAMMALIAN TARGET OF RAPAMYCIN; NELFINAVIR; RAPAMYCIN DERIVATIVE; SORAFENIB; TANESPIMYCIN; TIPIFARNIB; TIRAPAZAMINE; TRASTUZUMAB;

AUTOPHAGY; CANCER THERAPY; CARCINOGENESIS; CELL DEATH; CELL SURVIVAL; DRUG MECHANISM; ENZYME ACTIVATION; GENE CONTROL; GENE EXPRESSION; HUMAN; HYPOXIA; NONHUMAN; OXYGEN SENSING; PRIORITY JOURNAL; PROTEIN FOLDING; PROTEIN PROCESSING; REVIEW; RNA TRANSLATION; TUMOR GROWTH;

CELL HYPOXIA; HUMANS; HYPOXIA-INDUCIBLE FACTOR 1, ALPHA SUBUNIT; NEOPLASMS; PROTEIN FOLDING; PROTEIN KINASES; SIGNAL TRANSDUCTION;

EID: 54549089738     PISSN: 1474175X     EISSN: 14741768     Source Type: Journal    
DOI: 10.1038/nrc2501     Document Type: Review

References (145)

1. Dewhirst, M. W., Cao, Y. & Moeller, B. Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nature Rev. Cancer 8, 425-437 (2008).
2. Guertin, D. A. & Sabatini, D. M. Defining the role of mTOR in cancer. Cancer Cell 12, 9-22 (2007).
3. Browne, G. J. & Proud, C. G. A novel mTOR-regulated phosphorylation site in elongation factor 2 kinase modulates the activity of the kinase and its binding to calmodulin. Mol. Cell. Biol. 24, 2986-2997 (2004).
4. Arsham, A. M., Howell, J. J. & Simon, M. C. A novel hypoxia-inducible factor-independent hypoxic response regulating mammalian target of rapamycin and its targets. J. Biol. Chem. 278, 29655-29660 (2003). This was the first study to show that exposure to hypoxia could block activation of mTOR in a HIF-independent manner.
5. Liu, L. et al. Hypoxia-induced energy stress regulates mRNA translation and cell growth. Mol. Cell 21, 521-531 (2006).
6. Brugarolas, J. et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev. 18, 2893-2904 (2004).
7. Reiling, J. H. & Hafen, E. The hypoxia-induced paralogs Scylla and Charybdis inhibit growth by down-regulating S6K activity upstream of TSC in Drosophila. Genes Dev. 18, 2879-2892 (2004).
8. Sofer, A., Lei, K., Johannessen, C. M. & Ellisen, L. W. Regulation of mTOR and cell growth in response to energy stress by REDD1. Mol. Cell. Biol. 25, 5834-5845 (2005). References 6 and 8 demonstrated that mTOR inhibition during hypoxia is partly dependent on REDD1 signaling to TSC1-TSC2. This also provided a link between HIF and mTOR regulation
9. DeYoung, M. P., Horak, P., Sofer, A., Sgroi, D. & Ellisen, L. W. Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev. 22, 239-251 (2008).
10. Bernardi, R. et al. PML inhibits HIF-1α translation and neoangiogenesis through repression of mTOR. Nature 442, 779-785 (2006).
11. Li, Y. et al. Bnip3 mediates the hypoxia-induced inhibition on mammalian target of rapamycin by interacting with Rheb. J. Biol. Chem. 282, 35803-35813 (2007).
12. Hay, N. & Sonenberg, N. Upstream and downstream of mTOR. Genes Dev. 18, 1926-1945 (2004).
13. Dostie, J., Ferraiuolo, M., Pause, A., Adam, S. A. & Sonenberg, N. A novel shuttling protein, 4E-T, mediates the nuclear import of the mRNA 5′ cap-binding protein, eIF4E. EMBO J. 19, 3142-3156 (2000).
14. Koritzinsky, M. et al. Gene expression during acute and prolonged hypoxia is regulated by distinct mechanisms of translational control. EMBO J. 25, 1114-1125 (2006). This study demonstrated that hypoxia leads to both rapid and sustained inhibition of mRNA translation and that this influences gene expression during hypoxia through both mTOR- and UPR-dependent pathways.
15. Ferraiuolo, M. A. et al. A role for the eIF4E-binding protein 4E-T in P-body formation and mRNA decay. J. Cell Biol. 170, 913-924 (2005).
16. Freyer, J. P. Rates of oxygen consumption for proliferating and quiescent cells isolated from multicellular tumor spheroids. Adv. Exp. Med. Biol. 345, 335-342 (1994).
17. Graeber, T. G. et al. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379, 88-91 (1996).
18. Connolly, E., Braunstein, S., Formenti, S. & Schneider, R. J. Hypoxia inhibits protein synthesis through a 4E-BP1 and elongation factor 2 kinase pathway controlled by mTOR and uncoupled in breast cancer cells. Mol. Cell. Biol. 26, 3955-3965 (2006). This study suggests that mTOR activation during moderate hypoxia may act as a barrier to tumorigenesis, which is lost in advanced breast cancer.
19. Kaper, F., Dornhoefer, N. & Giaccia, A. J. Mutations in the PI3K/PTEN/TSC2 pathway contribute to mammalian target of rapamycin activity and increased translation under hypoxic conditions. Cancer Res. 66, 1561-1569 (2006).
20. Koritzinsky, M. et al. Phosphorylation of eIF2α is required for mRNA translation inhibition and survival during moderate hypoxia. Radiother. Oncol. 83, 353-361 (2007).
21. Magagnin, M. G. et al. The mTOR target 4E-BP1 contributes to differential protein expression during normoxia and hypoxia through changes in mRNA translation efficiency. Proteomics (2008).
22. Richter, J. D. & Sonenberg, N. Regulation of cap-dependent translation by eIF4E inhibitory proteins. Nature 433, 477-480 (2005).
23. Braunstein, S. et al. A hypoxia-controlled cap-dependent to cap-independent translation switch in breast cancer. Mol. Cell 28, 501-512 (2007). This study indicates that hypoxia contributes to changes in translation, which promote adverse phenotypes in advanced cancers. It also suggests that, in advanced cancer, hypoxic cells need to maintain regulation over cap-dependent translation.
24. Sowter, H. M., Ratcliffe, P. J., Watson, P., Greenberg, A. H. & Harris, A. L. HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors. Cancer Res. 61, 6669-6673 (2001).
25. Giatromanolaki, A. et al. BNIP3 expression is linked with hypoxia-regulated protein expression and with poor prognosis in non-small cell lung cancer. Clin. Cancer Res. 10, 5566-5571 (2004).
26. Giatromanolaki, A., Koukourakis, M. I., Gatter, K. C., Harris, A. L. & Sivridis, E. BNIP3 expression in endometrial cancer relates to active hypoxia inducible factor 1alpha pathway and prognosis. J. Clin. Pathol. 61, 217-220 (2008).
27. Tan, E. Y. et al. BNIP3 as a progression marker in primary human breast cancer; opposing functions in in situ versus invasive cancer. Clin. Cancer Res. 13, 467-474 (2007).
28. Erler, J. T. et al. Hypoxia-mediated down-regulation of Bid and Bax in tumors occurs via hypoxia-inducible factor 1-dependent and -independent mechanisms and contributes to drug resistance. Mol. Cell. Biol. 24, 2875-2889 (2004).
29. Mizushima, N. Autophagy: process and function. Genes Dev. 21, 2861-2873 (2007).
30. Azad, M. B. et al. Hypoxia induces autophagic cell death in apoptosis-competent cells through a mechanism involving BNIP3. Autophagy 4, 195-204 (2008).
31. Degenhardt, K. et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 10, 51-64 (2006).
32. Zhang, H. et al. Mitochondrial autophagy is a HIF-1-dependent adaptive metabolic response to hypoxia. J. Biol. Chem. 283, 10892-10903 (2008).
33. Adhami, F. et al. Cerebral ischemia-hypoxia induces intravascular coagulation and autophagy. Am. J. Pathol. 169, 566-583 (2006).
34. Yan, L. et al. Autophagy in chronically ischemic myocardium. Proc. Natl Acad. Sci. USA 102, 13807-13812 (2005).
35. Ravikumar, B. et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nature Genet. 36, 585-595 (2004).
36. Papandreou, I., Lim, A. L., Laderoute, K. & Denko, N. C. Hypoxia signals autophagy in tumor cells via AMPK activity, independent of HIF-1, BNIP3, and BNIP3L. Cell Death Differ. 15, 1572-1581 (2008).
37. Maiuri, M. C. et al. Functional and physical interaction between Bcl-XL and a BH3-like domain in Beclin-1. EMBO J. 26, 2527-2539 (2007).
38. Ron, D. & Walter, P. Signal integration in the endoplasmic reticulum unfolded protein response. Nature Rev. Mol. Cell Biol. 8, 519-529 (2007).
39. Zhang, K. & Kaufman, R. J. Protein folding in the endoplasmic reticulum and the unfolded protein response. Handb. Exp. Pharmacol. 172, 69-91 (2006).
40. 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 eIF2α. Mol. Cell. Biol. 22, 7405-7416 (2002). This study showed that both severe and moderate hypoxia can activate the PERK-EIF2α arm of the UPR and that this is important for hypoxia tolerance.
41. Ma, Y. & Hendershot, L. M. Delineation of a negative feedback regulatory loop that controls protein translation during endoplasmic reticulum stress. J. Biol. Chem. 278, 34864-34873 (2003).
42. Bi, M. et al. ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. EMBO J. 24, 3470-3481 (2005). This study demonstrated that activation of the UPR protects cells against hypoxic stress both in vitro and in vivo. Inhibition of PERK reduced tumour hypoxia and prevented growth of tumour xenografts.
43. Scheuner, D. et al. Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Mol. Cell 7, 1165-1176 (2001).
44. Romero-Ramirez, L. et al. XBP1 is essential for survival under hypoxic conditions and is required for tumor growth. Cancer Res. 64, 5943-5947 (2004). This paper showed that the IRE1-XBP1 arm of the UPR is also activated during hypoxia and contributes to hypoxia tolerance and tumour growth.
45. Davies, M. P. et al. Expression and splicing of the unfolded protein response gene XBP-1 are significantly associated with clinical outcome of endocrine-treated breast cancer. Int. J. Cancer 123, 85-88 (2008).
46. Ma, Y. & Hendershot, L. M. The role of the unfolded protein response in tumour development: friend or foe? Nature Rev. Cancer 4, 966-977 (2004).
47. Denoyelle, C. et al. Anti-oncogenic role of the endoplasmic reticulum differentially activated by mutations in the MAPK pathway. Nature Cell Biol. 8, 1053-1063 (2006).
48. Kraggerud, S. M., Sandvik, J. A. & Pettersen, E. O. Regulation of protein synthesis in human cells exposed to extreme hypoxia. Anticancer Res. 15, 683-686 (1995).
49. Vattem, K. M. & Wek, R. C. Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. Proc. Natl Acad. Sci. USA 101, 11269-11274 (2004).
50. Lu, P. D., Harding, H. P. & Ron, D. Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response. J. Cell Biol. 167, 27-33 (2004). This paper demonstrated the mechanism whereby certain mRNA transcripts can be preferentially translated under conditions that activate the UPR, such as hypoxia.
51. Blais, J. D. et al. Activating transcription factor 4 is translationally regulated by hypoxic stress. Mol. Cell. Biol. 24, 7469-7482 (2004).
52. Ameri, K. et al. Anoxic induction of ATF-4 through HIF-1-independent pathways of protein stabilization in human cancer cells. Blood 103, 1876-1882 (2004).
53. Blais, J. D. et al. Perk-dependent translational regulation promotes tumor cell adaptation and angiogenesis in response to hypoxic stress. Mol. Cell. Biol. 26, 9517-9532 (2006).
54. Murphy, B. J., Laderoute, K. R., Short, S. M. & Sutherland, R. M. The identification of heme oxygenase as a major hypoxic stress protein in Chinese hamster ovary cells. Br. J. Cancer 64, 69-73 (1991).
55. Roll, D. E., Murphy, B. J., Laderoute, K. R., Sutherland, R. M. & Smith, H. C. Oxygen regulated 80 kDa protein and glucose regulated 78 kDa protein are identical. Mol. Cell. Biochem. 103, 141-148 (1991).
56. Wilson, R. E. & Sutherland, R. M. Enhanced synthesis of specific proteins, RNA, and DNA caused by hypoxia and reoxygenation. Int. J. Radiat. Oncol. Biol. Phys. 16, 957-961 (1989).
57. Gess, B. et al. The cellular oxygen tension regulates expression of the endoplasmic oxidoreductase ERO1-Lα. Eur. J. Biochem. 270, 2228-2235 (2003).
58. Tanaka, S., Uehara, T. & Nomura, Y. Up-regulation of protein-disulfide isomerase in response to hypoxia/brain ischemia and its protective effect against apoptotic cell death. J. Biol. Chem. 275, 10388-10393 (2000).
59. Drogat, B. et al. IRE1 signaling is essential for ischemia-induced vascular endothelial growth factor-A expression and contributes to angiogenesis and tumor growth in vivo. Cancer Res. 67, 6700-6707 (2007).
60. May, D. et al. Ero1-L α plays a key role in a HIF-1-mediated pathway to improve disulfide bond formation and VEGF secretion under hypoxia: implication for cancer. Oncogene 24, 1011-1020 (2005).
61. Anelli, T. & Sitia, R. Protein quality control in the early secretory pathway. EMBO J. 27, 315-327 (2008).
62. Qi, X., Okuma, Y., Hosoi, T., Kaneko, M. & Nomura, Y. Induction of murine HRD1 in experimental cerebral ischemia. Brain Res. Mol. Brain Res. 130, 30-38 (2004).
63. Magagnin, M. G. et al. Proteomic analysis of gene expression following hypoxia and reoxygenation reveals proteins involved in the recovery from endoplasmic reticulum and oxidative stress. Radiother. Oncol. 83, 340-345 (2007).
64. Kouroku, Y. et al. ER stress (PERK/eIF2α phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation. Cell Death Differ. 14, 230-239 (2007).
65. Ogata, M. et al. Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol. Cell. Biol. 26, 9220-9231 (2006).
66. Bernales, S., McDonald, K. L. & Walter, P. Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol. 4, e423 (2006).
67. Leber, J. H., Bernales, S. & Walter, P. IRE1-independent gain control of the unfolded protein response. PLoS Biol. 2, E235 (2004).
68. Hetz, C. et al. Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1α. Science 312, 572-576 (2006).
69. Zinszner, H. et al. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev. 12, 982-995 (1998).
70. Marciniak, S. J. et al. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev. 18, 3066-3077 (2004).
71. Zundel, W. et al. Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev. 14, 391-396 (2000).
72. Brugarolas, J. B., Vazquez, F., Reddy, A., Sellers, W. R. & Kaelin, W. G. Jr. TSC2 regulates VEGF through mTOR-dependent and -independent pathways. Cancer Cell 4, 147-158 (2003).
73. Mazure, N. M., Chen, E. Y., Laderoute, K. R. & Giaccia, A. J. Induction of vascular endothelial growth factor by hypoxia is modulated by a phosphatidylinositol 3-kinase/Akt signaling pathway in Ha-ras-transformed cells through a hypoxia inducible factor-1 transcriptional element. Blood 90, 3322-3331 (1997).
74. Zhong, H. et al. Modulation of hypoxia-inducible factor 1α expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res. 60, 1541-1545 (2000).
75. Laughner, E., Taghavi, P., Chiles, K., Mahon, P. C. & Semenza, G. L. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1α (HIF-1α) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol. Cell. Biol. 21, 3995-4004 (2001). This study was one of the first to provide a link between receptor tyrosine kinase signalling through mTOR to regulate HIF.
76. Hudson, C. C. et al. Regulation of hypoxia-inducible factor 1α expression and function by the mammalian target of rapamycin. Mol. Cell. Biol. 22, 7004-7014 (2002).
77. Thomas, G. V. et al. Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nature Med. 12, 122-127 (2006).
78. Land, S. C. & Tee, A. R. Hypoxia-inducible factor 1α is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif. J. Biol. Chem. 282, 20534-20543 (2007).
79. Gorlach, A. et al. Efficient translation of mouse hypoxia-inducible factor-1α under normoxic and hypoxic conditions. Biochim. Biophys. Acta 1493, 125-134 (2000).
80. Stein, I. et al. Translation of vascular endothelial growth factor mRNA by internal ribosome entry: implications for translation under hypoxia. Mol. Cell. Biol. 18, 3112-3119 (1998). This study identified an internal ribosome entry site in VEGFA, which can promote its selective synthesis under conditions where mTOR is inhibited.
81. Lang, K. J., Kappel, A. & Goodall, G. J. Hypoxia-inducible factor-1α mRNA contains an internal ribosome entry site that allows efficient translation during normoxia and hypoxia. Mol. Biol. Cell 13, 1792-1801 (2002).
82. Bert, A. G., Grepin, R., Vadas, M. A. & Goodall, G. J. Assessing IRES activity in the HIF-1α and other cellular 5′ UTRs. RNA 12, 1074-1083 (2006).
83. Young, R. M. et al. Hypoxia-mediated selective mRNA translation by an internal ribosome entry site independent mechanism. J. Biol. Chem. 283, 16309-16319 (2008).
84. Hardwick, J. S., Kuruvilla, F. G., Tong, J. K., Shamji, A. F. & Schreiber, S. L. Rapamycin-modulated transcription defines the subset of nutrient-sensitive signaling pathways directly controlled by the Tor proteins. Proc. Natl Acad. Sci. USA 96, 14866-14870 (1999).
85. Peng, T., Golub, T. R. & Sabatini, D. M. The immunosuppressant rapamycin mimics a starvation-like signal distinct from amino acid and glucose deprivation. Mol. Cell. Biol. 22, 5575-5584 (2002).
86. Edinger, A. L., Linardic, C. M., Chiang, G. G., Thompson, C. B. & Abraham, R. T. Differential effects of rapamycin on mammalian target of rapamycin signaling functions in mammalian cells. Cancer Res. 63, 8451-8460 (2003).
87. Semenza, G. L. Targeting HIF-1 for cancer therapy. Nature Rev. Cancer 3, 721-732 (2003).
88. Zhang, H. et al. HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell 11, 407-420 (2007).
89. DeBerardinis, R. J., Lum, J. J., Hatzivassiliou, G. & Thompson, C. B. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 7, 11-20 (2008).
90. Dang, C. V., Kim, J. W., Gao, P. & Yustein, J. The interplay between MYC and HIF in cancer. Nature Rev. Cancer 8, 51-56 (2008).
91. Gordan, J. D., Thompson, C. B. & Simon, M. C. HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. Cancer Cell 12, 108-113 (2007).
92. Corn, P. G. et al. Mxi1 is induced by hypoxia in a HIF-1-dependent manner and protects cells from c-Myc-induced apoptosis. Cancer Biol. Ther. 4, 1285-1294 (2005).
93. Gordan, J. D., Bertout, J. A., Hu, C. J., Diehl, J. A. & Simon, M. C. HIF-2α promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell 11, 335-347 (2007).
94. Karantza-Wadsworth, V. et al. Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev. 21, 1621-1635 (2007).
95. Mathew, R., Karantza-Wadsworth, V. & White, E. Role of autophagy in cancer. Nature Rev. Cancer 7, 961-967 (2007).
96. 2+ increases. Cell Calcium 36, 187-199 (2004).
97. Hoyer-Hansen, M. & Jaattela, M. Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium. Cell Death Differ. 14, 1576-1582 (2007).
98. Sakaki, K., Wu, J. & Kaufman, R. J. Protein kinase C-θ is required for autophagy in response to stress in the endoplasmic reticulum. J. Biol. Chem. 283, 15370-15380 (2008).
99. Ozcan, U. et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306, 457-461 (2004).
100. Ozcan, U. et al. Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis. Mol. Cell 29, 541-551 (2008).
101. Harding, H. P. et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol. Cell 11, 619-633 (2003). This study provides evidence to suggest that UPR activation and upregulation of ATF4 is an important mediator of sensitivity to oxidative stress.
102. Koditz, J. et al. Oxygen-dependent ATF-4 stability is mediated by the PHD3 oxygen sensor. Blood 110, 3610-3617 (2007).
103. Maxwell, P. H. The HIF pathway in cancer. Semin. Cell Dev. Biol. 16, 523-530 (2005).
104. Koritzinsky, M. & Wouters, B. G. Hypoxia and regulation of messenger RNA translation. Methods Enzymol. 435, 247-273 (2007).
105. Kulshreshtha, R. et al. A microRNA signature of hypoxia. Mol. Cell. Biol. 27, 1859-1867 (2007).
106. Hebert, C., Norris, K., Scheper, M. A., Nikitakis, N. & Sauk, J. J. High mobility group A2 is a target for miRNA-98 in head and neck squamous cell carcinoma. Mol. Cancer 6, 5 (2007).
107. Fasanaro, P. et al. MicroRNA-210 modulates endothelial cell response to hypoxia and inhibits the receptor tyrosine-kinase ligand Ephrin-A3. J. Biol. Chem. 283, 15878-15883 (2008).
108. Hua, Z. et al. MiRNA-directed regulation of VEGF and other angiogenic factors under hypoxia. PLoS ONE 1, e116 (2006).
109. Giannakakis, A. et al. miR-210 links hypoxia with cell cycle regulation and is deleted in human epithelial ovarian cancer. Cancer Biol. Ther. 7, 255-264 (2007).
110. Camps, C. et al. hsa-miR-210 is induced by hypoxia and is an independent prognostic factor in breast cancer. Clin. Cancer Res. 14, 1340-1348 (2008).
111. 2 may serve as the final electron acceptor to drive disulfide bond formation in the ER.
112. Gray, L. H., Conger, A. D., Ebert, M., Hornsey, S. & Scott, O. C. The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br. J. Radiol. 26, 638-648 (1953).
113. Brown, J. M. & Wilson, W. R. Exploiting tumour hypoxia in cancer treatment. Nature Rev. Cancer 4, 437-447 (2004).
114. Brown, J. M. SR 4233 (tirapazamine): a new anticancer drug exploiting hypoxia in solid tumours. Br. J. Cancer 67, 1163-1170 (1993).
115. Melillo, G. Targeting hypoxia cell signaling for cancer therapy. Cancer Metastasis Rev. 26, 341-352 (2007).
116. Weppler, S. A. et al. Response of U87 glioma xenografts treated with concurrent rapamycin and fractionated radiotherapy: possible role for thrombosis. Radiother. Oncol. 82, 96-104 (2007).
117. Guba, M. et al. Rapamycin induces tumor-specific thrombosis via tissue factor in the presence of VEGF. Blood 105, 4463-4469 (2005).
118. Jain, R. K. Molecular regulation of vessel maturation. Nature Med. 9, 685-693 (2003).
119. Gupta, A. K. et al. The HIV protease inhibitor nelfinavir downregulates Akt phosphorylation by inhibiting proteasomal activity and inducing the unfolded protein response. Neoplasia 9, 271-278 (2007).
120. Pyrko, P. et al. HIV-1 protease inhibitors nelfinavir and atazanavir induce malignant glioma death by triggering endoplasmic reticulum stress. Cancer Res. 67, 10920-10928 (2007).
121. Gupta, A. K., Cerniglia, G. J., Mick, R., McKenna, W. G. & Muschel, R. J. HIV protease inhibitors block Akt signaling and radiosensitize tumor cells both in vitro and in vivo. Cancer Res. 65, 8256-8265 (2005).
122. Pore, N. et al. Nelfinavir down-regulates hypoxia-inducible factor 1α and VEGF expression and increases tumor oxygenation: implications for radiotherapy. Cancer Res. 66, 9252-9259 (2006).
123. Gills, J. J. et al. Nelfinavir, A lead HIV protease inhibitor, is a broad-spectrum, anticancer agent that induces endoplasmic reticulum stress, autophagy, and apoptosis in vitro and in vivo. Clin. Cancer Res. 13, 5183-5194 (2007).
124. Luwor, R. B., Lu, Y., Li, X., Mendelsohn, J. & Fan, Z. The antiepidermal growth factor receptor monoclonal antibody cetuximab/C225 reduces hypoxia-inducible factor-1α, leading to transcriptional inhibition of vascular endothelial growth factor expression. Oncogene 24, 4433-4441 (2005).
125. Huang, S. M. & Harari, P. M. Modulation of radiation response after epidermal growth factor receptor blockade in squamous cell carcinomas: inhibition of damage repair, cell cycle kinetics, and tumor angiogenesis. Clin. Cancer Res. 6, 2166-2174 (2000).
126. + tumors. Cancer Chemother. Pharmacol. 26 Mar 2008 (doi:10.1007/s00280-008-0729-3).
127. Guan, H., Jia, S. F., Zhou, Z., Stewart, J. & Kleinerman, E. S. Herceptin down-regulates HER-2/neu and vascular endothelial growth factor expression and enhances taxol-induced cytotoxicity of human Ewing's sarcoma cells in vitro and in vivo. Clin. Cancer Res. 11, 2008-2017 (2005).
128. Lu, Y., Liang, K., Li, X. & Fan, Z. Responses of cancer cells with wild-type or tyrosine kinase domain-mutated epidermal growth factor receptor (EGFR) to EGFR-targeted therapy are linked to downregulation of hypoxia-inducible factor-1α. Mol. Cancer 6, 63 (2007).
129. Warburton, C. et al. Treatment of HER-2/neu overexpressing breast cancer xenograft models with trastuzumab (Herceptin) and gefitinib (ZD1839): drug combination effects on tumor growth, HER-2/neu and epidermal growth factor receptor expression, and viable hypoxic cell fraction. Clin. Cancer Res. 10, 2512-2524 (2004).
130. Solomon, B. et al. Modulation of intratumoral hypoxia by the epidermal growth factor receptor inhibitor gefitinib detected using small animal PET imaging. Mol. Cancer Ther. 4, 1417-1422 (2005).
131. Hirata, A. et al. ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase. Cancer Res. 62, 2554-2560 (2002).
132. Vlahovic, G. et al. Treatment with imatinib improves drug delivery and efficacy in NSCLC xenografts. Br. J. Cancer 97, 735-740 (2007).
133. Murphy, D. A. et al. Inhibition of tumor endothelial ERK activation, angiogenesis, and tumor growth by sorafenib (BAY43-9006). Am. J. Pathol. 169, 1875-1885 (2006).
134. Del Bufalo, D. et al. Antiangiogenic potential of the mammalian target of rapamycin inhibitor temsirolimus. Cancer Res. 66, 5549-5554 (2006).
135. Wan, X., Shen, N., Mendoza, A., Khanna, C. & Helman, L. J. CCI-779 inhibits rhabdomyosarcoma xenograft growth by an antiangiogenic mechanism linked to the targeting of mTOR/Hif-1α/VEGF signaling. Neoplasia 8, 394-401 (2006).
136. Huynh, H., Teo, C. C. & Soo, K. C. Bevacizumab and rapamycin inhibit tumor growth in peritoneal model of human ovarian cancer. Mol. Cancer Ther. 6, 2959-2966 (2007).
137. Shi, Y. et al. Farnesyltransferase inhibitor effects on prostate tumor micro-environment and radiation survival. Prostate 62, 69-82 (2005).
138. Delmas, C. et al. The farnesyltransferase inhibitor R115777 reduces hypoxia and matrix metalloproteinase 2 expression in human glioma xenograft. Clin. Cancer Res. 9, 6062-6068 (2003).
139. Birle, D. C. & Hedley, D. W. Suppression of the hypoxia-inducible factor-1 response in cervical carcinoma xenografts by proteasome inhibitors. Cancer Res. 67, 1735-1743 (2007).
140. Kaluz, S., Kaluzova, M. & Stanbridge, E. J. Proteasomal inhibition attenuates transcriptional activity of hypoxia-inducible factor 1 (HIF-1) via specific effect on the HIF-1α C-terminal activation domain. Mol. Cell. Biol. 26, 5895-5907 (2006).
141. Roccaro, A. M. et al. Bortezomib mediates antiangiogenesis in multiple myeloma via direct and indirect effects on endothelial cells. Cancer Res. 66, 184-191 (2006).
142. Brignole, C. et al. Effect of bortezomib on human neuroblastoma cell growth, apoptosis, and angiogenesis. J. Natl Cancer Inst. 98, 1142-1157 (2006).
143. Pore, N., Gupta, A. K., Cerniglia, G. J. & Maity, A. HIV protease inhibitors decrease VEGF/HIF-1α expression and angiogenesis in glioblastoma cells. Neoplasia 8, 889-895 (2006).
144. Isaacs, J. S. et al. Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1α - degradative pathway. J. Biol. Chem. 277, 29936-29944 (2002).
145. Mabjeesh, N. J. et al. Geldanamycin induces degradation of hypoxia-inducible factor 1α protein via the proteosome pathway in prostate cancer cells. Cancer Res. 62, 2478-2482 (2002).