Advertisement

HIF-1α and Cancer Therapy

  • Mei Yee Koh
  • Taly R. Spivak-Kroizman
  • Garth PowisEmail author
Chapter
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 180)

Abstract

Most solid tumors develop regions of hypoxia as they grow and outstrip their blood supply. In order to survive in the stressful hypoxic environment, tumor cells have developed a coordinated set of responses orchestrating their adaptation to hypoxia. The outcomes of the cellular responses to hypoxia are aggressive disease, resistance to therapy, and decreased patient survival. A critical mediator of the hypoxic response is the transcription factor hypoxia-inducible factor 1 (HIF-1) that upregulates expression of proteins that promote angiogenesis, anaerobic metabolism, and many other survival pathways. Regulation of HIF-1α, a component of the HIF-1 heterodimer, occurs at multiple levels including translation, degradation, and transcriptional activation, and serves as a testimony to the central role of HIF-1. Studies demonstrating the importance of HIF-1α expression for tumor survival have made HIF-1α an attractive target for cancer therapy. The growing l.ist of pharmacological inhibitors of HIF-1 and their varied targets mirrors the complex molecular mechanisms controlling HIF-1. In this chapter, we summarize recent findings regarding the regulation of HIF-1α and the progress made in identifying new therapeutic agents that inhibit HIF-1α.

Keywords

Cancer Stem Cell HDAC Inhibitor Downstream Gene Expression Benzyl Indazole 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Aknowledgments Supported by NIH grants CA0179094, CA095060, CA0179094 and CA109552.

References

  1. Adhikary S, Eilers M (2005) Transcriptional regulation and transformation by Myc proteins. Nat Rev Mol Cell Biol 6:635–645PubMedCrossRefGoogle Scholar
  2. An WG, Kanekal M, Simon MC, Maltepe E, Blagosklonny MV, Neckers LM (1998) Stabilization of wild-type p53 by hypoxia-inducible factor 1alpha. Nature 392:405–408PubMedCrossRefGoogle Scholar
  3. Arany Z, Huang LE, Eckner R, Bhattacharya S, Jiang C, Goldberg MA, Bunn HF, Livingston DM (1996) An essential role for p300/CBP in the cellular response to hypoxia. Proc Natl Acad Sci U S A 93:12969–12973PubMedCrossRefGoogle Scholar
  4. Barnhart BC, Simon MC (2007) Metastasis and stem cell pathways. Cancer Metastasis Rev 26:261–271PubMedCrossRefGoogle Scholar
  5. Berchner-Pfannschmidt U, Petrat F, Doege K, Trinidad B, Freitag P, Metzen E, de Groot H, Fandrey J (2004) Chelation of cellular calcium modulates hypoxia-inducible gene expression through activation of hypoxia-inducible factor-1alpha. J Biol Chem 279:44976–44986PubMedCrossRefGoogle Scholar
  6. Bergers G, Benjamin LE (2003) Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3:401–410PubMedCrossRefGoogle Scholar
  7. Bernardi R, Guernah I, Jin D, Grisendi S, Alimonti A, Teruya-Feldstein J, Cordon-Cardo C, Simon MC, Rafii S, Pandolfi PP (2006) PML inhibits HIF-1alpha translation and neoangiogenesis through repression of mTOR. Nature 442:779–785PubMedCrossRefGoogle Scholar
  8. Berra E, Milanini J, Richard DE, Le Gall M, Vinals F, Gothie E, Roux D, Pages G, Pouyssegur J (2000) Signaling angiogenesis via p42/p44 MAP kinase and hypoxia. Biochem Pharmacol 60:1171–1178PubMedCrossRefGoogle Scholar
  9. Bert AG, Grepin R, Vadas MA, Goodall GJ (2006) Assessing IRES activity in the HIF-1alpha and other cellular 5’ UTRs. Rna 12:1074–1083PubMedCrossRefGoogle Scholar
  10. Blouw B, Song H, Tihan T, Bosze J, Ferrara N, Gerber HP, Johnson RS, Bergers G (2003) The hypoxic response of tumors is dependent on their microenvironment. Cancer Cell 4:133–146PubMedCrossRefGoogle Scholar
  11. Braunstein S, Karpisheva K, Pola C, Goldberg J, Hochman T, Yee H, Cangiarella J, Arju R, Formenti SC, Schneider RJ (2007) A hypoxia-controlled cap-dependent to cap-independent translation switch in breast cancer. Mol Cell 28:501–512PubMedCrossRefGoogle Scholar
  12. Bristow RG, Hill RP (2008) Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nat Rev Cancer 8:180–192PubMedCrossRefGoogle Scholar
  13. Brown JM, Giaccia AJ (1998) The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res 58:1408–1416PubMedGoogle Scholar
  14. Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, Ellisen LW, Kaelin WG Jr (2004) Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 18:2893–2904PubMedCrossRefGoogle Scholar
  15. Bruick RK (2000) Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia. Proc Natl Acad Sci U S A 97:9082–9087PubMedCrossRefGoogle Scholar
  16. Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P, Koch CJ, Ratcliffe P, Moons L, Jain RK, Collen D, Keshert E, Keshet E (1998) Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394:485–490PubMedCrossRefGoogle Scholar
  17. Carrero P, Okamoto K, Coumailleau P, O’Brien S, Tanaka H, Poellinger L (2000) Redox-regulated recruitment of the transcriptional coactivators CREB-binding protein and SRC-1 to hypoxia-inducible factor 1alpha. Mol Cell Biol 20:402–415PubMedCrossRefGoogle Scholar
  18. Chang H, Shyu KG, Lee CC, Tsai SC, Wang BW, Hsien Lee Y, Lin S (2003) GL331 inhibits HIF-1alpha expression in a lung cancer model. Biochem Biophys Res Commun 302:95–100PubMedCrossRefGoogle Scholar
  19. Chang Q, Qin R, Huang T, Gao J, Feng Y (2006) Effect of antisense hypoxia-inducible factor 1alpha on progression, metastasis, and chemosensitivity of pancreatic cancer. Pancreas 32:297–305PubMedCrossRefGoogle Scholar
  20. Chen J, Zhao S, Nakada K, Kuge Y, Tamaki N, Okada F, Wang J, Shindo M, Higashino F, Takeda K, Asaka M, Katoh H, Sugiyama T, Hosokawa M, Kobayashi M (2003) Dominant-negative hypoxia-inducible factor-1 alpha reduces tumorigenicity of pancreatic cancer cells through the suppression of glucose metabolism. Am J Pathol 162:1283–1291PubMedGoogle Scholar
  21. Chun YS, Yeo EJ, Choi E, Teng CM, Bae JM, Kim MS, Park JW (2001) Inhibitory effect of YC-1 on the hypoxic induction of erythropoietin and vascular endothelial growth factor in Hep3B cells. Biochem Pharmacol 61:947–954PubMedCrossRefGoogle Scholar
  22. Chun YS, Yeo EJ, Park JW (2004) Versatile pharmacological actions of YC-1: anti-platelet to anticancer. Cancer Lett 207:1–7PubMedCrossRefGoogle Scholar
  23. Corn PG, Ricci MS, Scata KA, Arsham AM, Simon MC, Dicker DT, El-Deiry WS (2005) Mxi1 is induced by hypoxia in a HIF-1-dependent manner and protects cells from c-Myc-induced apoptosis. Cancer Biol Ther 4:1285–1294PubMedGoogle Scholar
  24. Dang CV, Kim JW, Gao P, Yustein J (2008) The interplay between MYC and HIF in cancer. Nat Rev Cancer 8:51–56PubMedCrossRefGoogle Scholar
  25. Dang DT, Chen F, Gardner LB, Cummins JM, Rago C, Bunz F, Kantsevoy SV, Dang LH (2006) Hypoxia-inducible factor-1alpha promotes nonhypoxia-mediated proliferation in colon cancer cells and xenografts. Cancer Res 66:1684–1936PubMedCrossRefGoogle Scholar
  26. Del Bufalo D, Ciuffreda L, Trisciuoglio D, Desideri M, Cognetti F, Zupi G, Milella M (2006) Antiangiogenic potential of the Mammalian target of rapamycin inhibitor temsirolimus. Cancer Res 66:5549–5554PubMedCrossRefGoogle Scholar
  27. Escuin D, Kline ER, Giannakakou P (2005) Both microtubule-stabilizing and microtubule-destabilizing drugs inhibit hypoxia-inducible factor-1alpha accumulation and activity by disrupting microtubule function. Cancer Res 65:9021–9028PubMedCrossRefGoogle Scholar
  28. Fath DM, Kong X, Liang D, Lin Z, Chou A, Jiang Y, Fang J, Caro J, Sang N (2006) Histone deacetylase inhibitors repress the transactivation potential of hypoxia-inducible factors independently of direct acetylation of HIF-alpha. J Biol Chem 281:13612–13619PubMedCrossRefGoogle Scholar
  29. Galban S, Kuwano Y, Pullmann R Jr, Martindale JL, Kim HH, Lal A, Abdelmohsen K, Yang X, Dang Y, Liu JO, Lewis SM, Holcik M, Gorospe M (2008) RNA-binding proteins HuR and PTB promote the translation of hypoxia-inducible factor 1alpha. Mol Cell Biol 28:93–107PubMedCrossRefGoogle Scholar
  30. Giaccia AJ, Kastan MB (1998) The complexity of p53 modulation: emerging patterns from divergent signals. Genes Dev 12:2973–2983PubMedCrossRefGoogle Scholar
  31. Giordano FJ, Johnson RS (2001) Angiogenesis: the role of the microenvironment in flipping the switch. Curr Opin Genet Dev 11:35–40PubMedCrossRefGoogle Scholar
  32. Gordan JD, Bertout JA, Hu CJ, Diehl JA, Simon MC (2007) HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell 11:335–347PubMedCrossRefGoogle Scholar
  33. Graeber TG, Peterson JF, Tsai M, Monica K, Fornace AJ Jr, Giaccia AJ (1994) Hypoxia induces accumulation of p53 protein, but activation of a G1-phase checkpoint by low-oxygen conditions is independent of p53 status. Mol Cell Biol 14:6264–6277PubMedGoogle Scholar
  34. Gray MJ, Zhang J, Ellis LM, Semenza GL, Evans DB, Watowich SS, Gallick GE (2005) HIF-1alpha, STAT3, CBP/p300 and Ref-1/APE are components of a transcriptional complex that regulates Src-dependent hypoxia-induced expression of VEGF in pancreatic and prostate carcinomas. Oncogene 24:3110–3120PubMedCrossRefGoogle Scholar
  35. Gu W, Shi XL, Roeder RG (1997) Synergistic activation of transcription by CBP and p53. Nature 387:819–823PubMedCrossRefGoogle Scholar
  36. Gu YZ, Moran SM, Hogenesch JB, Wartman L, Bradfield CA (1998) Molecular characterization and chromosomal localization of a third alpha-class hypoxia inducible factor subunit, HIF3alpha. Gene Expr 7:205–213PubMedGoogle Scholar
  37. Hagen T, Taylor CT, Lam F, Moncada S (2003) Redistribution of intracellular oxygen in hypoxia by nitric oxide: effect on HIF1alpha. Science 302:1975–1978PubMedCrossRefGoogle Scholar
  38. Han JY, Oh SH, Morgillo F, Myers JN, Kim E, Hong WK, Lee HY (2005) Hypoxia-inducible factor 1alpha and antiangiogenic activity of farnesyltransferase inhibitor SCH66336 in human aerodigestive tract cancer. J Natl Cancer Inst 97:1272–1286PubMedCrossRefGoogle Scholar
  39. Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, Ron D (2000) Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6:1099–1108PubMedCrossRefGoogle Scholar
  40. Holmquist-Mengelbier L, Fredlund E, Lofstedt T, Noguera R, Navarro S, Nilsson H, Pietras A, Vallon-Christersson J, Borg A, Gradin K, Poellinger L, Pahlman S (2006) Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype. Cancer Cell 10:413–423PubMedCrossRefGoogle Scholar
  41. Hu CJ, Wang LY, Chodosh LA, Keith B, Simon MC (2003) Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Mol Cell Biol 23:9361–9374PubMedCrossRefGoogle Scholar
  42. Huang LE (2008) Carrot and stick: HIF-alpha engages c-Myc in hypoxic adaptation. Cell Death Differ 15:672–677PubMedCrossRefGoogle Scholar
  43. Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, Giaccia AJ, Abraham RT (2002) Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 22:7004–7014PubMedCrossRefGoogle Scholar
  44. Hui AS, Bauer AL, Striet JB, Schnell PO, Czyzyk-Krzeska MF (2006) Calcium signaling stimulates translation of HIF-alpha during hypoxia. Faseb J 20:466–475PubMedCrossRefGoogle Scholar
  45. Hur E, Kim HH, Choi SM, Kim JH, Yim S, Kwon HJ, Choi Y, Kim DK, Lee MO, Park H (2002) Reduction of hypoxia-induced transcription through the repression of hypoxia-inducible factor-1alpha/aryl hydrocarbon receptor nuclear translocator DNA binding by the 90-kDa heat-shock protein inhibitor radicicol. Mol Pharmacol 62:975–982PubMedCrossRefGoogle Scholar
  46. Isaacs JS, Jung YJ, Mimnaugh EG, Martinez A, Cuttitta F, Neckers LM (2002) Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1 alpha-degradative pathway. J Biol Chem 277:29936–29944PubMedCrossRefGoogle Scholar
  47. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292:468–472PubMedCrossRefGoogle Scholar
  48. Jiang BH, Liu LZ (2008) PI3K/PTEN signaling in tumorigenesis and angiogenesis. Biochim Biophys Acta 1784:150–158PubMedGoogle Scholar
  49. Jiang BH, Rue E, Wang GL, Roe R, Semenza GL (1996) Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1. J Biol Chem 271:17771–17778PubMedCrossRefGoogle Scholar
  50. Jordan BF, Runquist M, Raghunand N, Baker A, Williams R, Kirkpatrick L, Powis G, Gillies RJ (2005) Dynamic contrast-enhanced and diffusion MRI show rapid and dramatic changes in tumor microenvironment in response to inhibition of HIF-1alpha using PX-478. Neoplasia 7:475–485PubMedCrossRefGoogle Scholar
  51. Kaelin WG (2007) Von hippel-lindau disease. Annu Rev Pathol 2:145–173PubMedCrossRefGoogle Scholar
  52. Kang SH, Cho HT, Devi S, Zhang Z, Escuin D, Liang Z, Mao H, Brat DJ, Olson JJ, Simons JW, Lavallee TM, Giannakakou P, Van Meir EG, Shim H (2006) Antitumor effect of 2-methoxyestradiol in a rat orthotopic brain tumor model. Cancer Res 66:11991–11997PubMedCrossRefGoogle Scholar
  53. Kim HL, Yeo EJ, Chun YS, Park JW (2006) A domain responsible for HIF-1alpha degradation by YC-1, a novel anticancer agent. Int J Oncol 29:255–260PubMedGoogle Scholar
  54. Kim JW, Gao P, Liu YC, Semenza GL, Dang CV (2007) Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1. Mol Cell Biol 27:7381–7393PubMedCrossRefGoogle Scholar
  55. Kim JY, Ahn HJ, Ryu JH, Suk K, Park JH (2004) BH3-only protein Noxa is a mediator of hypoxic cell death induced by hypoxia-inducible factor 1alpha. J Exp Med 199:113–124PubMedCrossRefGoogle Scholar
  56. Kim MS, Kwon HJ, Lee YM, Baek JH, Jang JE, Lee SW, Moon EJ, Kim HS, Lee SK, Chung HY, Kim CW, Kim KW (2001) Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nat Med 7:437–443PubMedCrossRefGoogle Scholar
  57. Koh MY, Darnay BG, Powis G (2008a) Hypoxia-associated factor, a novel E3-ubiquitin ligase, binds and ubiquitinates hypoxia-inducible factor 1alpha, leading to its oxygen-independent degradation. Mol Cell Biol 28:7081–7095PubMedCrossRefGoogle Scholar
  58. Koh MY, Spivak-Kroizman T, Venturini S, Welsh S, Williams RR, Kirkpatrick DL, Powis G (2008b) Molecular mechanisms for the activity of PX-478, an antitumor inhibitor of the hypoxia-inducible factor-1alpha. Mol Cancer Ther 7:90–100PubMedCrossRefGoogle Scholar
  59. Koh MY, Spivak-Kroizman TR, Powis G (2008c) HIF-1 regulation: not so easy come, easy go. Trends Biochem Sci 33(11):526–534CrossRefGoogle Scholar
  60. Koivunen P, Tiainen P, Hyvarinen J, Williams KE, Sormunen R, Klaus SJ, Kivirikko KI, Myllyharju J (2007) An endoplasmic reticulum transmembrane prolyl 4-hydroxylase is induced by hypoxia and acts on hypoxia-inducible factor alpha. J Biol Chem 282:30544–30552PubMedCrossRefGoogle Scholar
  61. Kong X, Lin Z, Liang D, Fath D, Sang N, Caro J (2006) Histone deacetylase inhibitors induce VHL and ubiquitin-independent proteasomal degradation of hypoxia-inducible factor 1alpha. Mol Cell Biol 26:2019–2028PubMedCrossRefGoogle Scholar
  62. Koshiji M, Kageyama Y, Pete EA, Horikawa I, Barrett JC, Huang LE (2004) HIF-1alpha induces cell cycle arrest by functionally counteracting Myc. Embo J 23:1949–1956PubMedCrossRefGoogle Scholar
  63. Kung AL, Zabludoff SD, France DS, Freedman SJ, Tanner EA, Vieira A, Cornell-Kennon S, Lee J, Wang B, Wang J, Memmert K, Naegeli HU, Petersen F, Eck MJ, Bair KW, Wood AW, Livingston DM (2004) Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway. Cancer Cell 6:33–43PubMedCrossRefGoogle Scholar
  64. Kurebayashi J, Otsuki T, Kurosumi M, Soga S, Akinaga S, Sonoo H (2001) A radicicol derivative, KF58333, inhibits expression of hypoxia-inducible factor-1alpha and vascular endothelial growth factor, angiogenesis and growth of human breast cancer xenografts. Jpn J Cancer Res 92:1342–1351PubMedGoogle Scholar
  65. Lando D, Peet DJ, Whelan DA, Gorman JJ, Whitelaw ML (2002) Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science 295:858–861PubMedCrossRefGoogle Scholar
  66. Lang KJD, Kappel A, Goodall GJ (2002) Hypoxia-inducible factor-1 contains an interna ribosome entry site that allows efficient translation during normoxia and hypoxia. Mol Biol Cell 13:1792–1801PubMedCrossRefGoogle Scholar
  67. Levine AJ (1997) p53, the cellular gatekeeper for growth and division. Cell 88:323–331PubMedCrossRefGoogle Scholar
  68. Li L, Lin X, Staver M, Shoemaker A, Semizarov D, Fesik SW, Shen Y (2005) Evaluating hypoxia-inducible factor-1alpha as a cancer therapeutic target via inducible RNA interference in vivo. Cancer Res 65:7249–7258PubMedCrossRefGoogle Scholar
  69. Li SH, Shin DH, Chun YS, Lee MK, Kim MS, Park JW (2008) A novel mode of action of YC-1 in HIF inhibition: stimulation of FIH-dependent p300 dissociation from HIF-1{alpha}. Mol Cancer Ther 7:3729–3738PubMedCrossRefGoogle Scholar
  70. Liang D, Kong X, Sang N (2006) Effects of histone deacetylase inhibitors on HIF-1. Cell Cycle 5:2430–2435PubMedGoogle Scholar
  71. Litz J, Krystal GW (2006) Imatinib inhibits c-Kit-induced hypoxia-inducible factor-1alpha activity and vascular endothelial growth factor expression in small cell lung cancer cells. Mol Cancer Ther 5:1415–1422PubMedCrossRefGoogle Scholar
  72. Liu Q, Moller U, Flugel D, Kietzmann T (2004) Induction of plasminogen activator inhibitor I gene expression by intracellular calcium via hypoxia-inducible factor-1. Blood 104:3993–4001PubMedCrossRefGoogle Scholar
  73. Liu YV, Baek JH, Zhang H, Diez R, Cole RN, Semenza GL (2007a) RACK1 competes with HSP90 for binding to HIF-1alpha and is required for O(2)-independent and HSP90 inhibitor-induced degradation of HIF-1alpha. Mol Cell 25:207–217PubMedCrossRefGoogle Scholar
  74. Liu YV, Hubbi ME, Pan F, McDonald KR, Mansharamani M, Cole RN, Liu JO, Semenza GL (2007b) Calcineurin promotes hypoxia-inducible factor 1alpha expression by dephosphorylating RACK1 and blocking RACK1 dimerization. J Biol Chem 282:37064–37073PubMedCrossRefGoogle Scholar
  75. Luwor RB, Lu Y, Li X, Mendelsohn J, Fan Z (2005) The antiepidermal growth factor receptor monoclonal antibody cetuximab/C225 reduces hypoxia-inducible factor-1 alpha, leading to transcriptional inhibition of vascular endothelial growth factor expression. Oncogene 24:4433–4441PubMedCrossRefGoogle Scholar
  76. Mabjeesh NJ, Escuin D, LaVallee TM, Pribluda VS, Swartz GM, Johnson MS, Willard MT, Zhong H, Simons JW, Giannakakou P (2003) 2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF. Cancer Cell 3:363–375PubMedCrossRefGoogle Scholar
  77. Mahon PC, Hirota K, Semenza GL (2001) FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev 15:2675–2686PubMedCrossRefGoogle Scholar
  78. Majumder PK, Febbo PG, Bikoff R, Berger R, Xue Q, McMahon LM, Manola J, Brugarolas J, McDonnell TJ, Golub TR, Loda M, Lane HA, Sellers WR (2004) mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med 10:594–601PubMedCrossRefGoogle Scholar
  79. Makino Y, Kanopka A, Wilson WJ, Tanaka H, Poellinger L (2002) Inhibitory PAS domain protein (IPAS) is a hypoxia-inducible splicing variant of the hypoxia-inducible factor-3alpha locus. J Biol Chem 277:32405–32408PubMedCrossRefGoogle Scholar
  80. Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Activation of the HIF pathway in cancer. Curr Opin Genet Dev 11:293–299PubMedCrossRefGoogle Scholar
  81. Mayerhofer M, Valent P, Sperr WR, Griffin JD, Sillaber C (2002) BCR/ABL induces expression of vascular endothelial growth factor and its transcriptional activator, hypoxia inducible factor-1alpha, through a pathway involving phosphoinositide 3-kinase and the mammalian target of rapamycin. Blood 100:3767–3775PubMedCrossRefGoogle Scholar
  82. Melillo G (2007) Targeting hypoxia cell signaling for cancer therapy. Cancer Metastasis Rev 26:341–352PubMedCrossRefGoogle Scholar
  83. Melillo G, Gutierrez M, Holkova B, Rapisarda A, Raffeld M, Horneffer Y, Chang R, Murgo AJ, Doroshow JH, Kummar S (2007) A pilot trial of topotecan administered orally in patients with advanced solid tumors expressing hypoxia inducible factor (HIF)- 1alpha. J Clin Oncol 25:14103Google Scholar
  84. Metzen E, Fandrey J, Jelkmann W (1999) Evidence against a major role for Ca2+ in hypoxia-induced gene expression in human hepatoma cells (Hep3B). J Physiol 517(Pt 3):651–657PubMedCrossRefGoogle Scholar
  85. Mie Lee Y, Kim SH, Kim HS, Jin Son M, Nakajima H, Jeong Kwon H, Kim KW (2003) Inhibition of hypoxia-induced angiogenesis by FK228, a specific histone deacetylase inhibitor, via suppression of HIF-1alpha activity. Biochem Biophys Res Commun 300:241–246PubMedCrossRefGoogle Scholar
  86. Mottet D, Michel G, Renard P, Ninane N, Raes M, Michiels C (2002) ERK and calcium in activation of HIF-1. Ann N Y Acad Sci 973:448–453PubMedCrossRefGoogle Scholar
  87. Nakayama K, Ronai Z (2004) Siah: new players in the cellular response to hypoxia. Cell Cycle 3:1345–1347PubMedGoogle Scholar
  88. Newcomb EW, Ali MA, Schnee T, Lan L, Lukyanov Y, Fowkes M, Miller DC, Zagzag D (2005) Flavopiridol downregulates hypoxia-mediated hypoxia-inducible factor-1alpha expression in human glioma cells by a proteasome-independent pathway: implications for in vivo therapy. Neuro Oncol 7:225–235PubMedCrossRefGoogle Scholar
  89. Nordsmark M, Hoyer M, Keller J, Nielsen OS, Jensen OM, Overgaard J (1996) The relationship between tumor oxygenation and cell proliferation in human soft tissue sarcomas. Int J Radiat Oncol Biol Phys 35:701–708PubMedGoogle Scholar
  90. Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE, Pavletich N, Chau V, Kaelin WG (2000) Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol 2:423–427PubMedCrossRefGoogle Scholar
  91. Pan Y, Oprysko PR, Asham AM, Koch CJ, Simon MC (2004) p53 cannot be induced by hypoxia alone but responds to the hypoxic microenvironment. Oncogene 23:4975–4983PubMedCrossRefGoogle Scholar
  92. Pardal R, Clarke MF, Morrison SJ (2003) Applying the principles of stem-cell biology to cancer. Nat Rev Cancer 3:895–902PubMedCrossRefGoogle Scholar
  93. Patiar S, Harris AL (2006) Role of hypoxia-inducible factor-1alpha as a cancer therapy target. Endocr Relat Cancer 13(Suppl 1):S61–S75PubMedCrossRefGoogle Scholar
  94. Pore N, Jiang Z, Gupta A, Cerniglia G, Kao GD, Maity A (2006) EGFR tyrosine kinase inhibitors decrease VEGF expression by both hypoxia-inducible factor (HIF)-1-independent and HIF-1-dependent mechanisms. Cancer Res 66:3197–3204PubMedCrossRefGoogle Scholar
  95. Powis G, Kirkpatrick L (2004) Hypoxia inducible factor-1alpha as a cancer drug target. Mol Cancer Ther 3:647–654PubMedGoogle Scholar
  96. Powis G, Wipf P, Lynch SM, Birmingham A, Kirkpatrick DL (2006) Molecular pharmacology and antitumor activity of palmarumycin-based inhibitors of thioredoxin reductase. Mol Cancer Ther 5:630–636PubMedCrossRefGoogle Scholar
  97. Rapisarda A, Uranchimeg B, Scudiero DA, Selby M, Sausville EA, Shoemaker RH, Melillo G (2002) Identification of small molecule inhibitors of hypoxia-inducible factor 1 transcriptional activation pathway. Cancer Res 62:4316–4324PubMedGoogle Scholar
  98. Rapisarda A, Uranchimeg B, Sordet O, Pommier Y, Shoemaker RH, Melillo G (2004a) Topoisomerase I-mediated inhibition of hypoxia-inducible factor 1: mechanism and therapeutic implications. Cancer Res 64:1475–1482PubMedCrossRefGoogle Scholar
  99. Rapisarda A, Zalek J, Hollingshead M, Braunschweig T, Uranchimeg B, Bonomi CA, Borgel SD, Carter JP, Hewitt SM, Shoemaker RH, Melillo G (2004b) Schedule-dependent inhibition of hypoxia-inducible factor-1alpha protein accumulation, angiogenesis, and tumor growth by topotecan in U251-HRE glioblastoma xenografts. Cancer Res 64:6845–6848PubMedCrossRefGoogle Scholar
  100. Ravi R, Mookerjee B, Bhujwalla ZM, Sutter CH, Artemov D, Zeng Q, Dillehay LE, Madan A, Semenza GL, Bedi A (2000) Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes Dev 14:34–44PubMedGoogle Scholar
  101. Richard DE, Berra E, Gothie E, Roux D, Pouyssegur J (1999) p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1alpha (HIF-1alpha) and enhance the transcriptional activity of HIF-1. J Biol Chem 274:32631–32637PubMedCrossRefGoogle Scholar
  102. Roe JS, Kim H, Lee SM, Kim ST, Cho EJ, Youn HD (2006) p53 stabilization and transactivation by a von Hippel-Lindau protein. Mol Cell 22:395–405PubMedCrossRefGoogle Scholar
  103. Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8:519–529PubMedCrossRefGoogle Scholar
  104. Ryan HE, Lo J, Johnson RS (1998) HIF-1 alpha is required for solid tumor formation and embryonic vascularization. Embo J 17:3005–3015PubMedCrossRefGoogle Scholar
  105. Ryan HE, Poloni M, McNulty W, Elson D, Gassmann M, Arbeit JM, Johnson RS (2000) Hypoxia-inducible factor-1alpha is a positive factor in solid tumor growth. Cancer Res 60:4010–4015PubMedGoogle Scholar
  106. Salnikow K, Kluz T, Costa M, Piquemal D, Demidenko ZN, Xie K, Blagosklonny MV (2002) The regulation of hypoxic genes by calcium involves c-Jun/AP-1, which cooperates with hypoxia-inducible factor 1 in response to hypoxia. Mol Cell Biol 22:1734–1741PubMedCrossRefGoogle Scholar
  107. Savai R, Schermuly RT, Voswinckel R, Renigunta A, Reichmann B, Eul B, Grimminger F, Seeger W, Rose F, Hanze J (2005) HIF-1alpha attenuates tumor growth in spite of augmented vascularization in an A549 adenocarcinoma mouse model. Int J Oncol 27:393–400PubMedGoogle Scholar
  108. Schepens B, Tinton SA, Bruynooghe Y, Beyaert R, Cornelis S (2005) The polypyrimidine tract-binding protein stimulates HIF-1alpha IRES-mediated translation during hypoxia. Nucleic Acids Res 33:6884–6894PubMedCrossRefGoogle Scholar
  109. Semenza G (2002) Signal transduction to hypoxia-inducible factor 1. Biochem Pharmacol 64:993–998PubMedCrossRefGoogle Scholar
  110. Semenza GL (2007) Evaluation of HIF-1 inhibitors as anticancer agents. Drug Discov Today 12:853–859PubMedCrossRefGoogle Scholar
  111. Semenza GL (2004) Intratumoral hypoxia, radiation resistance, and HIF-1. Cancer Cell 5:405–406PubMedCrossRefGoogle Scholar
  112. Semenza GL (1999) Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol 15:551–578PubMedCrossRefGoogle Scholar
  113. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732PubMedCrossRefGoogle Scholar
  114. Semenza GL, Wang GL (1992) A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 12:5447–5454PubMedGoogle Scholar
  115. Seta KA, Yuan Y, Spicer Z, Lu G, Bedard J, Ferguson TK, Pathrose P, Cole-Strauss A, Kaufhold A, Millhorn DE (2004) The role of calcium in hypoxia-induced signal transduction and gene expression. Cell Calcium 36:331–340PubMedCrossRefGoogle Scholar
  116. Shchors K, Evan G (2007) Tumor angiogenesis: cause or consequence of cancer? Cancer Res 67:7059–7061PubMedCrossRefGoogle Scholar
  117. Shoshani T, Faerman A, Mett I, Zelin E, Tenne T, Gorodin S, Moshel Y, Elbaz S, Budanov A, Chajut A, Kalinski H, Kamer I, Rozen A, Mor O, Keshet E, Leshkowitz D, Einat P, Skaliter R, Feinstein E (2002) Identification of a novel hypoxia-inducible factor 1-responsive gene, RTP801, involved in apoptosis. Mol Cell Biol 22:2283–2293PubMedCrossRefGoogle Scholar
  118. Simon MC (2006) Mitochondrial reactive oxygen species are required for hypoxic HIF alpha stabilization. Adv Exp Med Biol 588:165–170PubMedCrossRefGoogle Scholar
  119. Sowter HM, Ratcliffe PJ, Watson P, Greenberg AH, Harris AL (2001) HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors. Cancer Res 61:6669–6673PubMedGoogle Scholar
  120. Sun HC, Qiu ZJ, Liu J, Sun J, Jiang T, Huang KJ, Yao M, Huang C (2007) Expression of hypoxia-inducible factor-1 alpha and associated proteins in pancreatic ductal adenocarcinoma and their impact on prognosis. Int J Oncol 30:1359–1367PubMedGoogle Scholar
  121. Sun X, Kanwar JR, Leung E, Lehnert K, Wang D, Krissansen GW (2001) Gene transfer of antisense hypoxia inducible factor-1 alpha enhances the therapeutic efficacy of cancer immunotherapy. Gene Ther 8:638–645PubMedCrossRefGoogle Scholar
  122. Sun X, Kanwar JR, Leung E, Vale M, Krissansen GW (2003) Regression of solid tumors by engineered overexpression of von Hippel-Lindau tumor suppressor protein and antisense hypoxia-inducible factor-1alpha. Gene Ther 10:2081–2089PubMedCrossRefGoogle Scholar
  123. Sutherland TE, Anderson RL, Hughes RA, Altmann E, Schuliga M, Ziogas J, Stewart AG (2007) 2-Methoxyestradiol–a unique blend of activities generating a new class of anti-tumour/anti-inflammatory agents. Drug Discov Today 12:577–584PubMedCrossRefGoogle Scholar
  124. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676PubMedCrossRefGoogle Scholar
  125. Thomas GV, Tran C, Mellinghoff IK, Welsbie DS, Chan E, Fueger B, Czernin J, Sawyers CL (2006) Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nat Med 12:122–127PubMedCrossRefGoogle Scholar
  126. Thomlinson RH, Gray LH (1955) The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer 9:539–549PubMedGoogle Scholar
  127. Unruh A, Ressel A, Mohamed HG, Johnson RS, Nadrowitz R, Richter E, Katschinski DM, Wenger RH (2003) The hypoxia-inducible factor-1 alpha is a negative factor for tumor therapy. Oncogene 22:3213–3220PubMedCrossRefGoogle Scholar
  128. Vaupel P, Mayer A (2007) Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev 26:225–239PubMedCrossRefGoogle Scholar
  129. Wan X, Shen N, Mendoza A, Khanna C, Helman LJ (2006) CCI-779 inhibits rhabdomyosarcoma xenograft growth by an antiangiogenic mechanism linked to the targeting of mTOR/Hif-1alpha/VEGF signaling. Neoplasia 8:394–401PubMedCrossRefGoogle Scholar
  130. Wang GL, Jiang BH, Rue EA, Semenza GL (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A 92:5510–5514PubMedCrossRefGoogle Scholar
  131. Welsh S, Williams R, Kirkpatrick L, Paine-Murrieta G, Powis G (2004) Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1alpha. Mol Cancer Ther 3:233–244PubMedGoogle Scholar
  132. Welsh SJ, Bellamy WT, Briehl MM, Powis G (2002) The redox protein thioredoxin-1 (Trx-1) increases hypoxia-inducible factor 1alpha protein expression: Trx-1 overexpression results in increased vascular endothelial growth factor production and enhanced tumor angiogenesis. Cancer Res 62:5089–5095PubMedGoogle Scholar
  133. Welsh SJ, Koh MY, Powis G (2006) The hypoxic inducible stress response as a target for cancer drug discovery. Semin Oncol 33:486–497PubMedCrossRefGoogle Scholar
  134. Welsh SJ, Powis G (2003) Hypoxia inducible factor as a cancer drug target. Curr Cancer Drug Targets 3:391–405PubMedCrossRefGoogle Scholar
  135. Wenger RH, Camenisch G, Desbaillets I, Chilov D, Gassmann M (1998) Up-regulation of hypoxia-inducible factor-1alpha is not sufficient for hypoxic/anoxic p53 induction. Cancer Res 58:5678–5680PubMedGoogle Scholar
  136. Werno C, Zhou J, Brune B (2008) A23187, ionomycin and thapsigargin upregulate mRNA of HIF-1alpha via endoplasmic reticulum stress rather than a rise in intracellular calcium. J Cell Physiol 215:708–714PubMedCrossRefGoogle Scholar
  137. Wiesener MS, Jurgensen JS, Rosenberger C, Scholze CK, Horstrup JH, Warnecke C, Mandriota S, Bechmann I, Frei UA, Pugh CW, Ratcliffe PJ, Bachmann S, Maxwell PH, Eckardt KU (2003) Widespread hypoxia-inducible expression of HIF-2alpha in distinct cell populations of different organs. Faseb J 17:271–273PubMedGoogle Scholar
  138. Williams KJ, Telfer BA, Airley RE, Peters HP, Sheridan MR, van der Kogel AJ, Harris AL, Stratford IJ (2002) A protective role for HIF-1 in response to redox manipulation and glucose deprivation: implications for tumorigenesis. Oncogene 21:282–290PubMedCrossRefGoogle Scholar
  139. Yeo EJ, Chun YS, Cho YS, Kim J, Lee JC, Kim MS, Park JW (2003) YC-1: a potential anticancer drug targeting hypoxia-inducible factor 1. J Natl Cancer Inst 95:516–525PubMedCrossRefGoogle Scholar
  140. Young RM, Wang SJ, Gordan JD, Ji X, Liebhaber SA, Simon MC (2008) Hypoxia-mediated selective mRNA translation by an internal ribosome entry site-independent mechanism. J Biol Chem 283:16309–16319PubMedCrossRefGoogle Scholar
  141. Zhang H, Gao P, Fukuda R, Kumar G, Krishnamachary B, Zeller KI, Dang CV, Semenza GL (2007) HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell 11:407–420PubMedCrossRefGoogle Scholar
  142. Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu MM, Simons JW, Semenza GL (2000) Modulation of hypoxia-inducible factor 1alpha 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 60:1541–1545PubMedGoogle Scholar
  143. Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL, Simons JW (1999) Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res 59:5830–5835PubMedGoogle Scholar
  144. Zhou J, Callapina M, Goodall GJ, Brune B (2004) Functional integrity of nuclear factor kappaB, phosphatidylinositol 3’-kinase, and mitogen-activated protein kinase signaling allows tumor necrosis factor alpha-evoked Bcl-2 expression to provoke internal ribosome entry site-dependent translation of hypoxia-inducible factor 1alpha. Cancer Res 64:9041–9048PubMedCrossRefGoogle Scholar
  145. Zhou J, Kohl R, Herr B, Frank R, Brune B (2006) Calpain mediates a von Hippel-Lindau protein-independent destruction of hypoxia-inducible factor-1alpha. Mol Biol Cell 17:1549–1558PubMedCrossRefGoogle Scholar
  146. Zimmer M, Ebert BL, Neil C, Brenner K, Papaioannou I, Melas A, Tolliday N, Lamb J, Pantopoulos K, Golub T, Iliopoulos O (2008) Small-molecule inhibitors of HIF-2a translation link its 5’UTR iron-responsive element to oxygen sensing. Mol Cell 32:838–848PubMedCrossRefGoogle Scholar
  147. Zundel W, Schindler C, Haas-Kogan D, Koong A, Kaper F, Chen E, Gottschalk AR, Ryan HE, Johnson RS, Jefferson AB, Stokoe D, Giaccia AJ (2000) Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev 14:391–396PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  • Mei Yee Koh
  • Taly R. Spivak-Kroizman
  • Garth Powis
    • 1
    Email author
  1. 1.MD Anderson Cancer CenterHoustonUSA

Personalised recommendations