Skip to main content
Top
Published in: Cancer & Metabolism 1/2014

Open Access 01-12-2014 | Review

Hypoxia signaling pathways in cancer metabolism: the importance of co-selecting interconnected physiological pathways

Authors: Norma Masson, Peter J Ratcliffe

Published in: Cancer & Metabolism | Issue 1/2014

Login to get access

Abstract

Both tumor hypoxia and dysregulated metabolism are classical features of cancer. Recent analyses have revealed complex interconnections between oncogenic activation, hypoxia signaling systems and metabolic pathways that are dysregulated in cancer. These studies have demonstrated that rather than responding simply to error signals arising from energy depletion or tumor hypoxia, metabolic and hypoxia signaling pathways are also directly connected to oncogenic signaling mechanisms at many points. This review will summarize current understanding of the role of hypoxia inducible factor (HIF) in these networks. It will also discuss the role of these interconnected pathways in generating the cancer phenotype; in particular, the implications of switching massive pathways that are physiologically 'hard-wired’ to oncogenic mechanisms driving cancer.
Appendix
Available only for authorised users
Literature
1.
go back to reference Warburg O: The Metabolism of Tumours. 1930, London: Arnold Constable Warburg O: The Metabolism of Tumours. 1930, London: Arnold Constable
2.
go back to reference Weinhouse S: Glycolysis, respiration, and anomalous gene expression in experimental hepatomas: G.H.A. Clowes memorial lecture. Cancer Res. 1972, 32: 2007-2016.PubMed Weinhouse S: Glycolysis, respiration, and anomalous gene expression in experimental hepatomas: G.H.A. Clowes memorial lecture. Cancer Res. 1972, 32: 2007-2016.PubMed
3.
go back to reference Warburg O: The metabolism of carcinoma cells. J Cancer Res. 1925, 9: 148-163. 10.1158/jcr.1925.148. Warburg O: The metabolism of carcinoma cells. J Cancer Res. 1925, 9: 148-163. 10.1158/jcr.1925.148.
4.
go back to reference Weinhouse S: Changing perceptions of carbohydrate metabolism in tumors. Molecular Interrelations of Nutrition and Cancer. 1982, New York: Raven Press: Arnott MS, van Eys J, Wang Y-M, 167-181. Weinhouse S: Changing perceptions of carbohydrate metabolism in tumors. Molecular Interrelations of Nutrition and Cancer. 1982, New York: Raven Press: Arnott MS, van Eys J, Wang Y-M, 167-181.
5.
go back to reference Weber G: Differential carbohydrate metabolism in tumor and host. Molecular Interrelations of Nutrition and Cancer. 1982, New York: Raven Press: Arnott MS, van Eys J, Wang Y-M, 191-208. Weber G: Differential carbohydrate metabolism in tumor and host. Molecular Interrelations of Nutrition and Cancer. 1982, New York: Raven Press: Arnott MS, van Eys J, Wang Y-M, 191-208.
6.
go back to reference Wang T, Marquardt C, Foker J: Aerobic glycolysis during lymphocyte proliferation. Nature. 1976, 261: 702-705. 10.1038/261702a0.PubMed Wang T, Marquardt C, Foker J: Aerobic glycolysis during lymphocyte proliferation. Nature. 1976, 261: 702-705. 10.1038/261702a0.PubMed
7.
go back to reference Hume DA, Weidemann MJ: Role and regulation of glucose metabolism in proliferating cells. J Natl Cancer Inst. 1979, 62: 3-8.PubMed Hume DA, Weidemann MJ: Role and regulation of glucose metabolism in proliferating cells. J Natl Cancer Inst. 1979, 62: 3-8.PubMed
8.
go back to reference Semenza GL, Wang GL: 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. 1992, 12: 5447-5454.PubMedPubMedCentral Semenza GL, Wang GL: 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. 1992, 12: 5447-5454.PubMedPubMedCentral
9.
go back to reference Maxwell PH, Pugh CW, Ratcliffe PJ: Inducible operation of the erythropoietin 3′ enhancer in multiple cell lines: evidence for a widespread oxygen sensing mechanism. Proc Natl Acad Sci U S A. 1993, 90: 2423-2427. 10.1073/pnas.90.6.2423.PubMedPubMedCentral Maxwell PH, Pugh CW, Ratcliffe PJ: Inducible operation of the erythropoietin 3′ enhancer in multiple cell lines: evidence for a widespread oxygen sensing mechanism. Proc Natl Acad Sci U S A. 1993, 90: 2423-2427. 10.1073/pnas.90.6.2423.PubMedPubMedCentral
10.
go back to reference Firth JD, Ebert BL, Pugh CW, Ratcliffe PJ: Oxygen-regulated control elements in the phosphoglycerate kinase 1 and lactate dehydrogenase A genes: similarities with the erythropoeitin 3′ enhancer. Proc Natl Acad Sci U S A. 1994, 91: 6496-6500. 10.1073/pnas.91.14.6496.PubMedPubMedCentral Firth JD, Ebert BL, Pugh CW, Ratcliffe PJ: Oxygen-regulated control elements in the phosphoglycerate kinase 1 and lactate dehydrogenase A genes: similarities with the erythropoeitin 3′ enhancer. Proc Natl Acad Sci U S A. 1994, 91: 6496-6500. 10.1073/pnas.91.14.6496.PubMedPubMedCentral
11.
go back to reference Semenza GL, Roth PH, Fang H-M, Wang GL: Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem. 1994, 269: 23757-23763.PubMed Semenza GL, Roth PH, Fang H-M, Wang GL: Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem. 1994, 269: 23757-23763.PubMed
12.
go back to reference Ebert BL, Gleadle JM, O’Rourke JF, Bartlett SM, Poulton J, Ratcliffe PJ: Isoenzyme specific regulation of genes involved in energy metabolism by hypoxia, cobalt and desferrioxamine: similarities with the regulation of erythropoietin. Biochem J. 1995, 313: 809-814. Ebert BL, Gleadle JM, O’Rourke JF, Bartlett SM, Poulton J, Ratcliffe PJ: Isoenzyme specific regulation of genes involved in energy metabolism by hypoxia, cobalt and desferrioxamine: similarities with the regulation of erythropoietin. Biochem J. 1995, 313: 809-814.
13.
go back to reference Kaelin WGJ, Ratcliffe PJ: Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell. 2008, 30: 393-402. 10.1016/j.molcel.2008.04.009.PubMed Kaelin WGJ, Ratcliffe PJ: Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell. 2008, 30: 393-402. 10.1016/j.molcel.2008.04.009.PubMed
14.
go back to reference Semenza GL: Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci. 2012, 33: 207-214. 10.1016/j.tips.2012.01.005.PubMedPubMedCentral Semenza GL: Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci. 2012, 33: 207-214. 10.1016/j.tips.2012.01.005.PubMedPubMedCentral
15.
go back to reference Loenarz C, Schofield CJ: Physiological and biochemical aspects of hydroxylations and demethylations catalyzed by human 2-oxoglutarate oxygenases. Trends Biochem Sci. 2011, 36: 7-18. 10.1016/j.tibs.2010.07.002.PubMed Loenarz C, Schofield CJ: Physiological and biochemical aspects of hydroxylations and demethylations catalyzed by human 2-oxoglutarate oxygenases. Trends Biochem Sci. 2011, 36: 7-18. 10.1016/j.tibs.2010.07.002.PubMed
16.
go back to reference Myllyharju J: Prolyl 4-hydroxylases, master regulators of the hypoxia response. Acta Physiol. 2013, 208: 148-165. 10.1111/apha.12096. Myllyharju J: Prolyl 4-hydroxylases, master regulators of the hypoxia response. Acta Physiol. 2013, 208: 148-165. 10.1111/apha.12096.
17.
go back to reference Thomlinson RH, Gray LH: The histological structure of some human lung cancers and the possible implications for radio-therapy. Br J Cancer. 1955, 9: 539-549. 10.1038/bjc.1955.55.PubMedPubMedCentral Thomlinson RH, Gray LH: The histological structure of some human lung cancers and the possible implications for radio-therapy. Br J Cancer. 1955, 9: 539-549. 10.1038/bjc.1955.55.PubMedPubMedCentral
18.
go back to reference Shweiki D, Itin A, Soffer D, Keshet E: Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992, 359: 843-845. 10.1038/359843a0.PubMed Shweiki D, Itin A, Soffer D, Keshet E: Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992, 359: 843-845. 10.1038/359843a0.PubMed
19.
go back to reference Maxwell PH, Dachs GU, Gleadle JM, Nicholls LG, Harris AL, Stratford IJ, Hankinson O, Pugh CW, Ratcliffe PJ: Hypoxia inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc Natl Acad Sci U S A. 1997, 94: 8104-8109. 10.1073/pnas.94.15.8104.PubMedPubMedCentral Maxwell PH, Dachs GU, Gleadle JM, Nicholls LG, Harris AL, Stratford IJ, Hankinson O, Pugh CW, Ratcliffe PJ: Hypoxia inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc Natl Acad Sci U S A. 1997, 94: 8104-8109. 10.1073/pnas.94.15.8104.PubMedPubMedCentral
20.
go back to reference Semenza GL: HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev. 2010, 20: 51-56. 10.1016/j.gde.2009.10.009.PubMedPubMedCentral Semenza GL: HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev. 2010, 20: 51-56. 10.1016/j.gde.2009.10.009.PubMedPubMedCentral
21.
go back to reference Hockel M, Vaupel P: Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst. 2001, 93: 266-276. 10.1093/jnci/93.4.266.PubMed Hockel M, Vaupel P: Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst. 2001, 93: 266-276. 10.1093/jnci/93.4.266.PubMed
22.
go back to reference Lehmann S, Stiehl DP, Honer M, Dominietto M, Keist R, Kotevic I, Wollenick K, Ametamey S, Wenger RH, Rudin M: Longitudinal and multimodal in vivo imaging of tumor hypoxia and its downstream molecular events. Proc Natl Acad Sci U S A. 2009, 106: 14004-14009. 10.1073/pnas.0901194106.PubMedPubMedCentral Lehmann S, Stiehl DP, Honer M, Dominietto M, Keist R, Kotevic I, Wollenick K, Ametamey S, Wenger RH, Rudin M: Longitudinal and multimodal in vivo imaging of tumor hypoxia and its downstream molecular events. Proc Natl Acad Sci U S A. 2009, 106: 14004-14009. 10.1073/pnas.0901194106.PubMedPubMedCentral
23.
go back to reference Raleigh JA, Calkins-Adams DP, Rinker LH, Ballenger CA, Weissler MC, Fowler WC, Novotny DB, Varia MA: Hypoxia and vascular endothelial growth factor expression in human squamous cell carcinomas using pimonidazole as a hypoxia marker. Cancer Res. 1998, 58: 3765-3768.PubMed Raleigh JA, Calkins-Adams DP, Rinker LH, Ballenger CA, Weissler MC, Fowler WC, Novotny DB, Varia MA: Hypoxia and vascular endothelial growth factor expression in human squamous cell carcinomas using pimonidazole as a hypoxia marker. Cancer Res. 1998, 58: 3765-3768.PubMed
24.
go back to reference Sobhanifar S, Aquino-Parsons C, Stanbridge EJ, Olive P: Reduced expression of hypoxia-inducible factor-1alpha in perinecrotic regions of solid tumors. Cancer Res. 2005, 65: 7259-7266. 10.1158/0008-5472.CAN-04-4480.PubMed Sobhanifar S, Aquino-Parsons C, Stanbridge EJ, Olive P: Reduced expression of hypoxia-inducible factor-1alpha in perinecrotic regions of solid tumors. Cancer Res. 2005, 65: 7259-7266. 10.1158/0008-5472.CAN-04-4480.PubMed
25.
go back to reference Bernardi R, Guernah I, Jin D, Grisendi S, Alimonti A, Teruya-Feldstein J, Cordon-Cardo C, Simon MC, Rafii S, Pandolfi PP: PML inhibits HIF-1alpha translation and neoangiogenesis through repression of mTOR. Nature. 2006, 442: 779-785. 10.1038/nature05029.PubMed Bernardi R, Guernah I, Jin D, Grisendi S, Alimonti A, Teruya-Feldstein J, Cordon-Cardo C, Simon MC, Rafii S, Pandolfi PP: PML inhibits HIF-1alpha translation and neoangiogenesis through repression of mTOR. Nature. 2006, 442: 779-785. 10.1038/nature05029.PubMed
26.
go back to reference Shachar I, Cohen S, Marom A, Becker-Herman S: Regulation of CLL survival by hypoxia-inducible factor and its target genes. FEBS Lett. 2012, 586: 2906-2910. 10.1016/j.febslet.2012.07.016.PubMed Shachar I, Cohen S, Marom A, Becker-Herman S: Regulation of CLL survival by hypoxia-inducible factor and its target genes. FEBS Lett. 2012, 586: 2906-2910. 10.1016/j.febslet.2012.07.016.PubMed
27.
go back to reference Duran RV, Mackenzie ED, Boulahbel H, Frezza C, Heiserich L, Tardito S, Bussolati O, Rocha S, Hall MN, Gottlieb E: HIF-independent role of prolyl hydroxylases in the cellular response to amino acids. Oncogene. 2013, 32: 4549-4556. 10.1038/onc.2012.465.PubMedPubMedCentral Duran RV, Mackenzie ED, Boulahbel H, Frezza C, Heiserich L, Tardito S, Bussolati O, Rocha S, Hall MN, Gottlieb E: HIF-independent role of prolyl hydroxylases in the cellular response to amino acids. Oncogene. 2013, 32: 4549-4556. 10.1038/onc.2012.465.PubMedPubMedCentral
28.
go back to reference Koivunen P, Hirsila M, Remes AM, Hassinen IE, Kivirikko KI, Myllyharju J: Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF. J Biol Chem. 2007, 282: 4524-4532. 10.1074/jbc.M610415200.PubMed Koivunen P, Hirsila M, Remes AM, Hassinen IE, Kivirikko KI, Myllyharju J: Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF. J Biol Chem. 2007, 282: 4524-4532. 10.1074/jbc.M610415200.PubMed
29.
go back to reference Hewitson KS, Lienard BM, McDonough MA, Clifton IJ, Butler D, Soares AS, Oldham NJ, McNeill LA, Schofield CJ: Structural and mechanistic studies on the inhibition of the hypoxia-inducible transcription factor hydroxylases by tricarboxylic acid cycle intermediates. J Biol Chem. 2007, 282: 3293-3301. 10.1074/jbc.M608337200.PubMed Hewitson KS, Lienard BM, McDonough MA, Clifton IJ, Butler D, Soares AS, Oldham NJ, McNeill LA, Schofield CJ: Structural and mechanistic studies on the inhibition of the hypoxia-inducible transcription factor hydroxylases by tricarboxylic acid cycle intermediates. J Biol Chem. 2007, 282: 3293-3301. 10.1074/jbc.M608337200.PubMed
30.
go back to reference O’Flaherty L, Adam J, Heather LC, Zhdanov AV, Chung YL, Miranda MX, Croft J, Olpin S, Clarke K, Pugh CW, Griffiths J, Papkovsky D, Ashrafian H, Ratcliffe PJ, Pollard PJ: Dysregulation of hypoxia pathways in fumarate hydratase-deficient cells is independent of defective mitochondrial metabolism. Hum Mol Genet. 2010, 19: 3844-3851. 10.1093/hmg/ddq305.PubMedPubMedCentral O’Flaherty L, Adam J, Heather LC, Zhdanov AV, Chung YL, Miranda MX, Croft J, Olpin S, Clarke K, Pugh CW, Griffiths J, Papkovsky D, Ashrafian H, Ratcliffe PJ, Pollard PJ: Dysregulation of hypoxia pathways in fumarate hydratase-deficient cells is independent of defective mitochondrial metabolism. Hum Mol Genet. 2010, 19: 3844-3851. 10.1093/hmg/ddq305.PubMedPubMedCentral
31.
go back to reference Pollard PJ, Briere JJ, Alam NA, Barwell J, Barclay E, Wortham NC, Hunt T, Mitchell M, Olpin S, Moat SJ, Hargreaves IP, Heales SJ, Chung YL, Griffiths JR, Dalgleish A, McGrath JA, Gleeson MJ, Hodgson SV, Poulsom R, Rustin P, Tomlinson IP: Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet. 2005, 14: 2231-2239. 10.1093/hmg/ddi227.PubMed Pollard PJ, Briere JJ, Alam NA, Barwell J, Barclay E, Wortham NC, Hunt T, Mitchell M, Olpin S, Moat SJ, Hargreaves IP, Heales SJ, Chung YL, Griffiths JR, Dalgleish A, McGrath JA, Gleeson MJ, Hodgson SV, Poulsom R, Rustin P, Tomlinson IP: Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet. 2005, 14: 2231-2239. 10.1093/hmg/ddi227.PubMed
32.
go back to reference Isaacs JS, Jung YJ, Mole DR, Lee S, Torres-Cabala C, Merino M, Trepel J, Zbar B, Toro J, Ratcliffe PJ, Linehan WM, Neckers L: HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell. 2005, 8: 143-153. 10.1016/j.ccr.2005.06.017.PubMed Isaacs JS, Jung YJ, Mole DR, Lee S, Torres-Cabala C, Merino M, Trepel J, Zbar B, Toro J, Ratcliffe PJ, Linehan WM, Neckers L: HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell. 2005, 8: 143-153. 10.1016/j.ccr.2005.06.017.PubMed
33.
go back to reference Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, Pan Y, Simon MC, Thompson CB, Gottlieb E: Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell. 2005, 7: 77-85. 10.1016/j.ccr.2004.11.022.PubMed Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, Pan Y, Simon MC, Thompson CB, Gottlieb E: Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell. 2005, 7: 77-85. 10.1016/j.ccr.2004.11.022.PubMed
34.
go back to reference Osada-Oka M, Hashiba Y, Akiba S, Imaoka S, Sato T: Glucose is necessary for stabilization of hypoxia-inducible factor-1alpha under hypoxia: contribution of the pentose phosphate pathway to this stabilization. FEBS Lett. 2010, 584: 3073-3079. 10.1016/j.febslet.2010.05.046.PubMed Osada-Oka M, Hashiba Y, Akiba S, Imaoka S, Sato T: Glucose is necessary for stabilization of hypoxia-inducible factor-1alpha under hypoxia: contribution of the pentose phosphate pathway to this stabilization. FEBS Lett. 2010, 584: 3073-3079. 10.1016/j.febslet.2010.05.046.PubMed
35.
go back to reference Sonveaux P, Copetti T, De Saedeleer CJ, Végran F, Verrax J, Kennedy KM, Moon EJ, Dhup S, Danhier P, Frérart F, Gallez B, Ribeiro A, Michiels C, Dewhirst MW, Feron O: Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis. PLoS One. 2012, 7: e33418-10.1371/journal.pone.0033418.PubMedPubMedCentral Sonveaux P, Copetti T, De Saedeleer CJ, Végran F, Verrax J, Kennedy KM, Moon EJ, Dhup S, Danhier P, Frérart F, Gallez B, Ribeiro A, Michiels C, Dewhirst MW, Feron O: Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis. PLoS One. 2012, 7: e33418-10.1371/journal.pone.0033418.PubMedPubMedCentral
36.
go back to reference Hunt TK, Aslam RS, Beckert S, Wagner S, Ghani QP, Hussain MZ, Roy S, Sen CK: Aerobically derived lactate stimulates revascularization and tissue repair via redox mechanisms. Antioxid Redox Signal. 2007, 9: 1115-1124. 10.1089/ars.2007.1674.PubMedPubMedCentral Hunt TK, Aslam RS, Beckert S, Wagner S, Ghani QP, Hussain MZ, Roy S, Sen CK: Aerobically derived lactate stimulates revascularization and tissue repair via redox mechanisms. Antioxid Redox Signal. 2007, 9: 1115-1124. 10.1089/ars.2007.1674.PubMedPubMedCentral
37.
go back to reference Lu H, Dalgard CL, Mohyeldin A, McFate T, Tait AS, Verma A: Reversible inactivation of HIF-1 prolyl hydroxylases allows cell metabolism to control basal HIF-1. J Biol Chem. 2005, 280: 41928-41939. 10.1074/jbc.M508718200.PubMed Lu H, Dalgard CL, Mohyeldin A, McFate T, Tait AS, Verma A: Reversible inactivation of HIF-1 prolyl hydroxylases allows cell metabolism to control basal HIF-1. J Biol Chem. 2005, 280: 41928-41939. 10.1074/jbc.M508718200.PubMed
38.
go back to reference Yang H, Ye D, Guan KL, Xiong Y: IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives. Clin Cancer Res. 2012, 18: 5562-5571. 10.1158/1078-0432.CCR-12-1773.PubMedPubMedCentral Yang H, Ye D, Guan KL, Xiong Y: IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives. Clin Cancer Res. 2012, 18: 5562-5571. 10.1158/1078-0432.CCR-12-1773.PubMedPubMedCentral
39.
go back to reference Rakheja D, Medeiros LJ, Bevan S, Chen W: The emerging role of d-2-hydroxyglutarate as an oncometabolite in hematolymphoid and central nervous system neoplasms. Front Oncol. 2013, 3: 169-PubMedPubMedCentral Rakheja D, Medeiros LJ, Bevan S, Chen W: The emerging role of d-2-hydroxyglutarate as an oncometabolite in hematolymphoid and central nervous system neoplasms. Front Oncol. 2013, 3: 169-PubMedPubMedCentral
40.
go back to reference Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, Cross JR, Fantin VR, Hedvat CV, Perl AE, Rabinowitz JD, Carroll M, Su SM, Sharp KA, Levine RL, Thompson CB: The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010, 17: 225-234. 10.1016/j.ccr.2010.01.020.PubMedPubMedCentral Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, Cross JR, Fantin VR, Hedvat CV, Perl AE, Rabinowitz JD, Carroll M, Su SM, Sharp KA, Levine RL, Thompson CB: The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010, 17: 225-234. 10.1016/j.ccr.2010.01.020.PubMedPubMedCentral
41.
go back to reference Chowdhury R, Yeoh KK, Tian YM, Hillringhaus L, Bagg EA, Rose NR, Leung IK, Li XS, Woon EC, Yang M, McDonough MA, King ON, Clifton IJ, Klose RJ, Claridge TD, Ratcliffe PJ, Schofield CJ, Kawamura A: The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 2011, 12: 463-469. 10.1038/embor.2011.43.PubMedPubMedCentral Chowdhury R, Yeoh KK, Tian YM, Hillringhaus L, Bagg EA, Rose NR, Leung IK, Li XS, Woon EC, Yang M, McDonough MA, King ON, Clifton IJ, Klose RJ, Claridge TD, Ratcliffe PJ, Schofield CJ, Kawamura A: The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 2011, 12: 463-469. 10.1038/embor.2011.43.PubMedPubMedCentral
42.
go back to reference Koivunen P, Lee S, Duncan CG, Lopez G, Lu G, Ramkissoon S, Losman JA, Joensuu P, Bergmann U, Gross S, Travins J, Weiss S, Looper R, Ligon KL, Verhaak RG, Yan H, Kaelin WG: Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature. 2012, 483: 484-488. 10.1038/nature10898.PubMedPubMedCentral Koivunen P, Lee S, Duncan CG, Lopez G, Lu G, Ramkissoon S, Losman JA, Joensuu P, Bergmann U, Gross S, Travins J, Weiss S, Looper R, Ligon KL, Verhaak RG, Yan H, Kaelin WG: Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature. 2012, 483: 484-488. 10.1038/nature10898.PubMedPubMedCentral
43.
go back to reference Toschi A, Lee E, Gadir N, Ohh M, Foster DA: Differential dependence of hypoxia-inducible factors 1 alpha and 2 alpha on mTORC1 and mTORC2. J Biol Chem. 2008, 283: 34495-34499. 10.1074/jbc.C800170200.PubMedPubMedCentral Toschi A, Lee E, Gadir N, Ohh M, Foster DA: Differential dependence of hypoxia-inducible factors 1 alpha and 2 alpha on mTORC1 and mTORC2. J Biol Chem. 2008, 283: 34495-34499. 10.1074/jbc.C800170200.PubMedPubMedCentral
44.
go back to reference Liu L, Cash TP, Jones RG, Keith B, Thompson CB, Simon MC: Hypoxia-induced energy stress regulates mRNA translation and cell growth. Mol Cell. 2006, 21: 521-531. 10.1016/j.molcel.2006.01.010.PubMedPubMedCentral Liu L, Cash TP, Jones RG, Keith B, Thompson CB, Simon MC: Hypoxia-induced energy stress regulates mRNA translation and cell growth. Mol Cell. 2006, 21: 521-531. 10.1016/j.molcel.2006.01.010.PubMedPubMedCentral
45.
go back to reference Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, Ellisen LW, Kaelin WG: Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev. 2004, 18: 2893-2904. 10.1101/gad.1256804.PubMedPubMedCentral Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, Ellisen LW, Kaelin WG: Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev. 2004, 18: 2893-2904. 10.1101/gad.1256804.PubMedPubMedCentral
46.
go back to reference DeYoung MP, Horak P, Sofer A, Sgroi D, Ellisen LW: Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev. 2008, 22: 239-251. 10.1101/gad.1617608.PubMedPubMedCentral DeYoung MP, Horak P, Sofer A, Sgroi D, Ellisen LW: Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev. 2008, 22: 239-251. 10.1101/gad.1617608.PubMedPubMedCentral
47.
go back to reference Geng H, Liu Q, Xue C, David LL, Beer TM, Thomas GV, Dai MS, Qian DZ: HIF1alpha protein stability is increased by acetylation at lysine 709. J Biol Chem. 2012, 287: 35496-35505. 10.1074/jbc.M112.400697.PubMedPubMedCentral Geng H, Liu Q, Xue C, David LL, Beer TM, Thomas GV, Dai MS, Qian DZ: HIF1alpha protein stability is increased by acetylation at lysine 709. J Biol Chem. 2012, 287: 35496-35505. 10.1074/jbc.M112.400697.PubMedPubMedCentral
48.
go back to reference Lim JH, Lee YM, Chun YS, Chen J, Kim JE, Park JW: Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. Mol Cell. 2010, 38: 864-878. 10.1016/j.molcel.2010.05.023.PubMed Lim JH, Lee YM, Chun YS, Chen J, Kim JE, Park JW: Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. Mol Cell. 2010, 38: 864-878. 10.1016/j.molcel.2010.05.023.PubMed
49.
go back to reference Xenaki G, Ontikatze T, Rajendran R, Stratford IJ, Dive C, Krstic-Demonacos M, Demonacos C: PCAF is an HIF-1alpha cofactor that regulates p53 transcriptional activity in hypoxia. Oncogene. 2008, 27: 5785-5796. 10.1038/onc.2008.192.PubMedPubMedCentral Xenaki G, Ontikatze T, Rajendran R, Stratford IJ, Dive C, Krstic-Demonacos M, Demonacos C: PCAF is an HIF-1alpha cofactor that regulates p53 transcriptional activity in hypoxia. Oncogene. 2008, 27: 5785-5796. 10.1038/onc.2008.192.PubMedPubMedCentral
50.
go back to reference Finley LW, Carracedo A, Lee J, Souza A, Egia A, Zhang J, Teruya-Feldstein J, Moreira PI, Cardoso SM, Clish CB, Pandolfi PP, Haigis MC: SIRT3 opposes reprogramming of cancer cell metabolism through HIF1alpha destabilization. Cancer Cell. 2011, 19: 416-428. 10.1016/j.ccr.2011.02.014.PubMedPubMedCentral Finley LW, Carracedo A, Lee J, Souza A, Egia A, Zhang J, Teruya-Feldstein J, Moreira PI, Cardoso SM, Clish CB, Pandolfi PP, Haigis MC: SIRT3 opposes reprogramming of cancer cell metabolism through HIF1alpha destabilization. Cancer Cell. 2011, 19: 416-428. 10.1016/j.ccr.2011.02.014.PubMedPubMedCentral
51.
go back to reference Zhong L, D’Urso A, Toiber D, Sebastian C, Henry RE, Vadysirisack DD, Guimaraes A, Marinelli B, Wikstrom JD, Nir T, Clish CB, Vaitheesvaran B, Iliopoulos O, Kurland I, Dor Y, Weissleder R, Shirihai OS, Ellisen LW, Espinosa JM, Mostoslavsky R: The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell. 2010, 140: 280-293. 10.1016/j.cell.2009.12.041.PubMedPubMedCentral Zhong L, D’Urso A, Toiber D, Sebastian C, Henry RE, Vadysirisack DD, Guimaraes A, Marinelli B, Wikstrom JD, Nir T, Clish CB, Vaitheesvaran B, Iliopoulos O, Kurland I, Dor Y, Weissleder R, Shirihai OS, Ellisen LW, Espinosa JM, Mostoslavsky R: The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell. 2010, 140: 280-293. 10.1016/j.cell.2009.12.041.PubMedPubMedCentral
52.
go back to reference Dioum EM, Chen R, Alexander MS, Zhang Q, Hogg RT, Gerard RD, Garcia JA: Regulation of hypoxia-inducible factor 2alpha signaling by the stress-responsive deacetylase sirtuin 1. Science. 2009, 324: 1289-1293. 10.1126/science.1169956.PubMed Dioum EM, Chen R, Alexander MS, Zhang Q, Hogg RT, Gerard RD, Garcia JA: Regulation of hypoxia-inducible factor 2alpha signaling by the stress-responsive deacetylase sirtuin 1. Science. 2009, 324: 1289-1293. 10.1126/science.1169956.PubMed
53.
go back to reference Laemmle A, Lechleiter A, Roh V, Schwarz C, Portmann S, Furer C, Keogh A, Tschan MP, Candinas D, Vorburger SA, Stroka D: Inhibition of SIRT1 impairs the accumulation and transcriptional activity of HIF-1alpha protein under hypoxic conditions. PLoS One. 2012, 7: e33433-10.1371/journal.pone.0033433.PubMedPubMedCentral Laemmle A, Lechleiter A, Roh V, Schwarz C, Portmann S, Furer C, Keogh A, Tschan MP, Candinas D, Vorburger SA, Stroka D: Inhibition of SIRT1 impairs the accumulation and transcriptional activity of HIF-1alpha protein under hypoxic conditions. PLoS One. 2012, 7: e33433-10.1371/journal.pone.0033433.PubMedPubMedCentral
54.
go back to reference Chen R, Dioum EM, Hogg RT, Gerard RD, Garcia JA: Hypoxia increases sirtuin 1 expression in a hypoxia-inducible factor-dependent manner. J Biol Chem. 2011, 286: 13869-13878. 10.1074/jbc.M110.175414.PubMedPubMedCentral Chen R, Dioum EM, Hogg RT, Gerard RD, Garcia JA: Hypoxia increases sirtuin 1 expression in a hypoxia-inducible factor-dependent manner. J Biol Chem. 2011, 286: 13869-13878. 10.1074/jbc.M110.175414.PubMedPubMedCentral
55.
go back to reference Knowles HJ, Raval RR, Harris AL, Ratcliffe PJ: Effect of ascorbate on the activity of hypoxia inducible factor (HIF) in cancer cells. Cancer Res. 2003, 63: 1764-1768.PubMed Knowles HJ, Raval RR, Harris AL, Ratcliffe PJ: Effect of ascorbate on the activity of hypoxia inducible factor (HIF) in cancer cells. Cancer Res. 2003, 63: 1764-1768.PubMed
56.
go back to reference Aapro M, Osterborg A, Gascon P, Ludwig H, Beguin Y: Prevalence and management of cancer-related anaemia, iron deficiency and the specific role of i.v. iron. Ann Oncol. 2012, 23: 1954-1962. 10.1093/annonc/mds112.PubMed Aapro M, Osterborg A, Gascon P, Ludwig H, Beguin Y: Prevalence and management of cancer-related anaemia, iron deficiency and the specific role of i.v. iron. Ann Oncol. 2012, 23: 1954-1962. 10.1093/annonc/mds112.PubMed
57.
go back to reference Nytko KJ, Maeda N, Schlafli P, Spielmann P, Wenger RH, Stiehl DP: Vitamin C is dispensable for oxygen sensing in vivo. Blood. 2011, 117: 5485-5493. 10.1182/blood-2010-09-307637.PubMedPubMedCentral Nytko KJ, Maeda N, Schlafli P, Spielmann P, Wenger RH, Stiehl DP: Vitamin C is dispensable for oxygen sensing in vivo. Blood. 2011, 117: 5485-5493. 10.1182/blood-2010-09-307637.PubMedPubMedCentral
58.
go back to reference Kuiper C, Molenaar IG, Dachs GU, Currie MJ, Sykes PH, Vissers MC: Low ascorbate levels are associated with increased hypoxia-inducible factor-1 activity and an aggressive tumor phenotype in endometrial cancer. Cancer Res. 2010, 70: 5749-5758. 10.1158/0008-5472.CAN-10-0263.PubMed Kuiper C, Molenaar IG, Dachs GU, Currie MJ, Sykes PH, Vissers MC: Low ascorbate levels are associated with increased hypoxia-inducible factor-1 activity and an aggressive tumor phenotype in endometrial cancer. Cancer Res. 2010, 70: 5749-5758. 10.1158/0008-5472.CAN-10-0263.PubMed
59.
go back to reference Eckard J, Dai J, Wu J, Jian J, Yang Q, Chen H, Costa M, Frenkel K, Huang X: Effects of cellular iron deficiency on the formation of vascular endothelial growth factor and angiogenesis. Iron deficiency and angiogenesis. Cancer Cell Int. 2010, 10: 28-PubMed Eckard J, Dai J, Wu J, Jian J, Yang Q, Chen H, Costa M, Frenkel K, Huang X: Effects of cellular iron deficiency on the formation of vascular endothelial growth factor and angiogenesis. Iron deficiency and angiogenesis. Cancer Cell Int. 2010, 10: 28-PubMed
60.
go back to reference Gerald D, Berra E, Frapart YM, Chan DA, Giaccia AJ, Mansuy D, Pouyssegur J, Yaniv M, Mechta-Grigoriou F: JunD reduces tumor angiogenesis by protecting cells from oxidative stress. Cell. 2004, 118: 781-794. 10.1016/j.cell.2004.08.025.PubMed Gerald D, Berra E, Frapart YM, Chan DA, Giaccia AJ, Mansuy D, Pouyssegur J, Yaniv M, Mechta-Grigoriou F: JunD reduces tumor angiogenesis by protecting cells from oxidative stress. Cell. 2004, 118: 781-794. 10.1016/j.cell.2004.08.025.PubMed
61.
go back to reference Gao P, Zhang H, Dinavahi R, Li F, Xiang Y, Raman V, Bhujwalla ZM, Felsher DW, Cheng L, Pevsner J, Lee LA, Semenza GL, Dang CV: HIF-dependent antitumorigenic effect of antioxidants in vivo. Cancer Cell. 2007, 12: 230-238. 10.1016/j.ccr.2007.08.004.PubMedPubMedCentral Gao P, Zhang H, Dinavahi R, Li F, Xiang Y, Raman V, Bhujwalla ZM, Felsher DW, Cheng L, Pevsner J, Lee LA, Semenza GL, Dang CV: HIF-dependent antitumorigenic effect of antioxidants in vivo. Cancer Cell. 2007, 12: 230-238. 10.1016/j.ccr.2007.08.004.PubMedPubMedCentral
62.
go back to reference Flashman E, Davies SL, Yeoh KK, Schofield CJ: Investigating the dependence of the hypoxia-inducible factor hydroxylases (factor inhibiting HIF and prolyl hydroxylase domain 2) on ascorbate and other reducing agents. Biochem J. 2010, 427: 135-142. 10.1042/BJ20091609.PubMed Flashman E, Davies SL, Yeoh KK, Schofield CJ: Investigating the dependence of the hypoxia-inducible factor hydroxylases (factor inhibiting HIF and prolyl hydroxylase domain 2) on ascorbate and other reducing agents. Biochem J. 2010, 427: 135-142. 10.1042/BJ20091609.PubMed
63.
go back to reference Klimova T, Chandel NS: Mitochondrial complex III regulates hypoxic activation of HIF. Cell Death Differ. 2008, 15: 660-666. 10.1038/sj.cdd.4402307.PubMed Klimova T, Chandel NS: Mitochondrial complex III regulates hypoxic activation of HIF. Cell Death Differ. 2008, 15: 660-666. 10.1038/sj.cdd.4402307.PubMed
64.
go back to reference Hagen T: Oxygen versus reactive oxygen in the regulation of HIF-1alpha: the balance tips. Biochem Res Int. 2012, 2012: 436981-PubMedPubMedCentral Hagen T: Oxygen versus reactive oxygen in the regulation of HIF-1alpha: the balance tips. Biochem Res Int. 2012, 2012: 436981-PubMedPubMedCentral
65.
go back to reference Masson N, Singleton RS, Sekirnik R, Trudgian DC, Ambrose LJ, Miranda MX, Tian YM, Kessler BM, Schofield CJ, Ratcliffe PJ: The FIH hydroxylase is a cellular peroxide sensor that modulates HIF transcriptional activity. EMBO Rep. 2012, 12: 251-257. Masson N, Singleton RS, Sekirnik R, Trudgian DC, Ambrose LJ, Miranda MX, Tian YM, Kessler BM, Schofield CJ, Ratcliffe PJ: The FIH hydroxylase is a cellular peroxide sensor that modulates HIF transcriptional activity. EMBO Rep. 2012, 12: 251-257.
66.
go back to reference Tian Y, Yeoh KK, Lee MK, Ericsson T, Kessler BM, Kramer HB, Edelmann MJ, William C, Pugh CW, Schofield CJ, Ratcliffe PJ: Differential sensitivity of HIF hydroxylation sites to hypoxia and hydroxylase inhibitors. J Biol Chem. 2011, 286: 13041-13051. 10.1074/jbc.M110.211110.PubMedPubMedCentral Tian Y, Yeoh KK, Lee MK, Ericsson T, Kessler BM, Kramer HB, Edelmann MJ, William C, Pugh CW, Schofield CJ, Ratcliffe PJ: Differential sensitivity of HIF hydroxylation sites to hypoxia and hydroxylase inhibitors. J Biol Chem. 2011, 286: 13041-13051. 10.1074/jbc.M110.211110.PubMedPubMedCentral
67.
go back to reference Dayan F, Roux D, Brahimi-Horn MC, Pouyssegur J, Mazure NM: The oxygen sensor factor-inhibiting hypoxia-inducible factor-1 controls expression of distinct genes through the bifunctional transcriptional character of hypoxia-inducible factor-1alpha. Cancer Res. 2006, 66: 3688-3698. 10.1158/0008-5472.CAN-05-4564.PubMed Dayan F, Roux D, Brahimi-Horn MC, Pouyssegur J, Mazure NM: The oxygen sensor factor-inhibiting hypoxia-inducible factor-1 controls expression of distinct genes through the bifunctional transcriptional character of hypoxia-inducible factor-1alpha. Cancer Res. 2006, 66: 3688-3698. 10.1158/0008-5472.CAN-05-4564.PubMed
68.
go back to reference Bonello S, Zahringer C, BelAiba RS, Djordjevic T, Hess J, Michiels C, Kietzmann T, Görlach A: Reactive oxygen species activate the HIF-1alpha promoter via a functional NFkappaB site. Arterioscler Thromb Vasc Biol. 2007, 27: 755-761. 10.1161/01.ATV.0000258979.92828.bc.PubMed Bonello S, Zahringer C, BelAiba RS, Djordjevic T, Hess J, Michiels C, Kietzmann T, Görlach A: Reactive oxygen species activate the HIF-1alpha promoter via a functional NFkappaB site. Arterioscler Thromb Vasc Biol. 2007, 27: 755-761. 10.1161/01.ATV.0000258979.92828.bc.PubMed
69.
go back to reference van Uden P, Kenneth NS, Webster R, Muller HA, Mudie S, Rocha S: Evolutionary conserved regulation of HIF-1beta by NF-kappaB. PLoS Genet. 2011, 7: e1001285-10.1371/journal.pgen.1001285.PubMedPubMedCentral van Uden P, Kenneth NS, Webster R, Muller HA, Mudie S, Rocha S: Evolutionary conserved regulation of HIF-1beta by NF-kappaB. PLoS Genet. 2011, 7: e1001285-10.1371/journal.pgen.1001285.PubMedPubMedCentral
70.
go back to reference Maranchie JK, Zhan Y: Nox4 is critical for hypoxia-inducible factor 2-alpha transcriptional activity in von Hippel-Lindau-deficient renal cell carcinoma. Cancer Res. 2005, 65: 9190-9193. 10.1158/0008-5472.CAN-05-2105.PubMedPubMedCentral Maranchie JK, Zhan Y: Nox4 is critical for hypoxia-inducible factor 2-alpha transcriptional activity in von Hippel-Lindau-deficient renal cell carcinoma. Cancer Res. 2005, 65: 9190-9193. 10.1158/0008-5472.CAN-05-2105.PubMedPubMedCentral
71.
go back to reference Block K, Gorin Y, Hoover P, Williams P, Chelmicki T, Clark RA, Yoneda T, Abboud HE: NAD(P)H oxidases regulate HIF-2alpha protein expression. J Biol Chem. 2007, 282: 8019-8026. 10.1074/jbc.M611569200.PubMed Block K, Gorin Y, Hoover P, Williams P, Chelmicki T, Clark RA, Yoneda T, Abboud HE: NAD(P)H oxidases regulate HIF-2alpha protein expression. J Biol Chem. 2007, 282: 8019-8026. 10.1074/jbc.M611569200.PubMed
72.
go back to reference Kaelin WG: The von Hippel-Lindau tumour suppressor protein: O2 sensing and cancer. Nat Rev Cancer. 2008, 8: 865-873. 10.1038/nrc2502.PubMed Kaelin WG: The von Hippel-Lindau tumour suppressor protein: O2 sensing and cancer. Nat Rev Cancer. 2008, 8: 865-873. 10.1038/nrc2502.PubMed
73.
go back to reference Knauth K, Bex C, Jemth P, Buchberger A: Renal cell carcinoma risk in type 2 von Hippel-Lindau disease correlates with defects in pVHL stability and HIF-1alpha interactions. Oncogene. 2006, 25: 370-377.PubMed Knauth K, Bex C, Jemth P, Buchberger A: Renal cell carcinoma risk in type 2 von Hippel-Lindau disease correlates with defects in pVHL stability and HIF-1alpha interactions. Oncogene. 2006, 25: 370-377.PubMed
74.
go back to reference Li L, Zhang L, Zhang X, Yan Q, Minamishima YA, Olumi AF, Mao M, Bartz S, Kaelin WG: Hypoxia-inducible factor linked to differential kidney cancer risk seen with type 2A and type 2B VHL mutations. Mol Cell Biol. 2007, 27: 5381-5392. 10.1128/MCB.00282-07.PubMedPubMedCentral Li L, Zhang L, Zhang X, Yan Q, Minamishima YA, Olumi AF, Mao M, Bartz S, Kaelin WG: Hypoxia-inducible factor linked to differential kidney cancer risk seen with type 2A and type 2B VHL mutations. Mol Cell Biol. 2007, 27: 5381-5392. 10.1128/MCB.00282-07.PubMedPubMedCentral
75.
go back to reference Pouyssegur J, Dayan F, Mazure NM: Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature. 2006, 441: 437-443. 10.1038/nature04871.PubMed Pouyssegur J, Dayan F, Mazure NM: Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature. 2006, 441: 437-443. 10.1038/nature04871.PubMed
76.
go back to reference Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL: HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1a (HIF-1a) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol. 2001, 21: 3995-4004. 10.1128/MCB.21.12.3995-4004.2001.PubMedPubMedCentral Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL: HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1a (HIF-1a) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol. 2001, 21: 3995-4004. 10.1128/MCB.21.12.3995-4004.2001.PubMedPubMedCentral
77.
go back to reference Pore N, Jiang Z, Shu HK, Bernhard E, Kao GD, Maity A: Akt1 activation can augment hypoxia-inducible factor-1alpha expression by increasing protein translation through a mammalian target of rapamycin-independent pathway. Mol Cancer Res. 2006, 4: 471-479. 10.1158/1541-7786.MCR-05-0234.PubMed Pore N, Jiang Z, Shu HK, Bernhard E, Kao GD, Maity A: Akt1 activation can augment hypoxia-inducible factor-1alpha expression by increasing protein translation through a mammalian target of rapamycin-independent pathway. Mol Cancer Res. 2006, 4: 471-479. 10.1158/1541-7786.MCR-05-0234.PubMed
78.
go back to reference Flugel D, Gorlach A, Michiels C, Kietzmann T: Glycogen synthase kinase 3 phosphorylates hypoxia-inducible factor 1alpha and mediates its destabilization in a VHL-independent manner. Mol Cell Biol. 2007, 27: 3253-3265. 10.1128/MCB.00015-07.PubMedPubMedCentral Flugel D, Gorlach A, Michiels C, Kietzmann T: Glycogen synthase kinase 3 phosphorylates hypoxia-inducible factor 1alpha and mediates its destabilization in a VHL-independent manner. Mol Cell Biol. 2007, 27: 3253-3265. 10.1128/MCB.00015-07.PubMedPubMedCentral
79.
go back to reference Sang N, Stiehl DP, Bohensky J, Leshchinsky I, Srinivas V, Caro J: MAPK signaling up-regulates the activity of hypoxia-inducible factors by its effects on p300. J Biol Chem. 2003, 278: 14013-14019. 10.1074/jbc.M209702200.PubMedPubMedCentral Sang N, Stiehl DP, Bohensky J, Leshchinsky I, Srinivas V, Caro J: MAPK signaling up-regulates the activity of hypoxia-inducible factors by its effects on p300. J Biol Chem. 2003, 278: 14013-14019. 10.1074/jbc.M209702200.PubMedPubMedCentral
80.
go back to reference Schmid T, Zhou J, Brüne B: HIF-1 and p53: communication of transcription factors under hypoxia. J Cell Mol Med. 2004, 8: 423-431. 10.1111/j.1582-4934.2004.tb00467.x.PubMed Schmid T, Zhou J, Brüne B: HIF-1 and p53: communication of transcription factors under hypoxia. J Cell Mol Med. 2004, 8: 423-431. 10.1111/j.1582-4934.2004.tb00467.x.PubMed
81.
go back to reference Sermeus A, Michiels C: Reciprocal influence of the p53 and the hypoxic pathways. Cell Death Dis. 2011, 2: e164-10.1038/cddis.2011.48.PubMedPubMedCentral Sermeus A, Michiels C: Reciprocal influence of the p53 and the hypoxic pathways. Cell Death Dis. 2011, 2: e164-10.1038/cddis.2011.48.PubMedPubMedCentral
82.
go back to reference Hansson LO, Friedler A, Freund S, Rudiger S, Fersht AR: Two sequence motifs from HIF-1a bind to the DNA-binding site of p53. Proc Natl Acad Sci U S A. 2002, 99: 10305-10309. 10.1073/pnas.122347199.PubMedPubMedCentral Hansson LO, Friedler A, Freund S, Rudiger S, Fersht AR: Two sequence motifs from HIF-1a bind to the DNA-binding site of p53. Proc Natl Acad Sci U S A. 2002, 99: 10305-10309. 10.1073/pnas.122347199.PubMedPubMedCentral
83.
go back to reference Schmid T, Zhou J, Köhl R, Brüne B: p300 relieves p53-evoked transcriptional repression of hypoxia-inducible factor-1 (HIF-1). Biochem J. 2004, 380: 289-295. 10.1042/BJ20031299.PubMedPubMedCentral Schmid T, Zhou J, Köhl R, Brüne B: p300 relieves p53-evoked transcriptional repression of hypoxia-inducible factor-1 (HIF-1). Biochem J. 2004, 380: 289-295. 10.1042/BJ20031299.PubMedPubMedCentral
84.
go back to reference Ravi R, Mookerjee B, Bhujwalla ZM, Sutter CH, Artemov D, Zeng Q, Dillehay LE, Madan A, Semenza GL, Bedi A: Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1a. Genes Dev. 2000, 14: 34-44.PubMedPubMedCentral Ravi R, Mookerjee B, Bhujwalla ZM, Sutter CH, Artemov D, Zeng Q, Dillehay LE, Madan A, Semenza GL, Bedi A: Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1a. Genes Dev. 2000, 14: 34-44.PubMedPubMedCentral
85.
go back to reference Morris MR, Hughes DJ, Tian YM, Ricketts CJ, Lau KW, Gentle D, Shuib S, Serrano-Fernandez P, Lubinski J, Wiesener MS, Pugh CW, Latif F, Ratcliffe PJ, Maher ER: Mutation analysis of hypoxia-inducible factors HIF1A and HIF2A in renal cell carcinoma. Anticancer Res. 2009, 29: 4337-4343.PubMed Morris MR, Hughes DJ, Tian YM, Ricketts CJ, Lau KW, Gentle D, Shuib S, Serrano-Fernandez P, Lubinski J, Wiesener MS, Pugh CW, Latif F, Ratcliffe PJ, Maher ER: Mutation analysis of hypoxia-inducible factors HIF1A and HIF2A in renal cell carcinoma. Anticancer Res. 2009, 29: 4337-4343.PubMed
86.
go back to reference Dalgliesh GL, Furge K, Greenman C, Chen L, Bignell G, Butler A, Davies H, Edkins S, Hardy C, Latimer C, Teague J, Andrews J, Barthorpe S, Beare D, Buck G, Campbell PJ, Forbes S, Jia M, Jones D, Knott H, Kok CY, Lau KW, Leroy C, Lin ML, McBride DJ, Maddison M, Maguire S, McLay K, Menzies A, Mironenko T: Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature. 2010, 463: 360-363. 10.1038/nature08672.PubMedPubMedCentral Dalgliesh GL, Furge K, Greenman C, Chen L, Bignell G, Butler A, Davies H, Edkins S, Hardy C, Latimer C, Teague J, Andrews J, Barthorpe S, Beare D, Buck G, Campbell PJ, Forbes S, Jia M, Jones D, Knott H, Kok CY, Lau KW, Leroy C, Lin ML, McBride DJ, Maddison M, Maguire S, McLay K, Menzies A, Mironenko T: Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature. 2010, 463: 360-363. 10.1038/nature08672.PubMedPubMedCentral
87.
go back to reference Shen C, Beroukhim R, Schumacher SE, Zhou J, Chang M, Signoretti S, Kaelin WG: Genetic and functional studies implicate HIF1alpha as a 14q kidney cancer suppressor gene. Cancer Discov. 2011, 1: 222-235. 10.1158/2159-8290.CD-11-0098.PubMedPubMedCentral Shen C, Beroukhim R, Schumacher SE, Zhou J, Chang M, Signoretti S, Kaelin WG: Genetic and functional studies implicate HIF1alpha as a 14q kidney cancer suppressor gene. Cancer Discov. 2011, 1: 222-235. 10.1158/2159-8290.CD-11-0098.PubMedPubMedCentral
88.
go back to reference Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, Gassmann M, Gearhart JD, Lawler AM, Yu AY, Semenza GL: Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev. 1998, 12: 149-162. 10.1101/gad.12.2.149.PubMedPubMedCentral Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, Gassmann M, Gearhart JD, Lawler AM, Yu AY, Semenza GL: Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev. 1998, 12: 149-162. 10.1101/gad.12.2.149.PubMedPubMedCentral
89.
go back to reference Ullah MS, Davies AJ, Halestrap AP: The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism. J Biol Chem. 2006, 281: 9030-9037. 10.1074/jbc.M511397200.PubMed Ullah MS, Davies AJ, Halestrap AP: The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism. J Biol Chem. 2006, 281: 9030-9037. 10.1074/jbc.M511397200.PubMed
90.
go back to reference Marin-Hernandez A, Gallardo-Perez JC, Ralph SJ, Rodriguez-Enriquez S, Moreno-Sanchez R: HIF-1alpha modulates energy metabolism in cancer cells by inducing over-expression of specific glycolytic isoforms. Mini Rev Med Chem. 2009, 9: 1084-1101. 10.2174/138955709788922610.PubMed Marin-Hernandez A, Gallardo-Perez JC, Ralph SJ, Rodriguez-Enriquez S, Moreno-Sanchez R: HIF-1alpha modulates energy metabolism in cancer cells by inducing over-expression of specific glycolytic isoforms. Mini Rev Med Chem. 2009, 9: 1084-1101. 10.2174/138955709788922610.PubMed
91.
go back to reference Minchenko O, Opentanova I, Minchenko D, Ogura T, Esumi H: Hypoxia induces transcription of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-4 gene via hypoxia-inducible factor-1alpha activation. FEBS Lett. 2004, 576: 14-20. 10.1016/j.febslet.2004.08.053.PubMed Minchenko O, Opentanova I, Minchenko D, Ogura T, Esumi H: Hypoxia induces transcription of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-4 gene via hypoxia-inducible factor-1alpha activation. FEBS Lett. 2004, 576: 14-20. 10.1016/j.febslet.2004.08.053.PubMed
92.
go back to reference Yi W, Clark PM, Mason DE, Keenan MC, Hill C, Goddard WA, Peters EC, Driggers EM, Hsieh-Wilson LC: Phosphofructokinase 1 glycosylation regulates cell growth and metabolism. Science. 2012, 337: 975-980. 10.1126/science.1222278.PubMedPubMedCentral Yi W, Clark PM, Mason DE, Keenan MC, Hill C, Goddard WA, Peters EC, Driggers EM, Hsieh-Wilson LC: Phosphofructokinase 1 glycosylation regulates cell growth and metabolism. Science. 2012, 337: 975-980. 10.1126/science.1222278.PubMedPubMedCentral
93.
go back to reference Luo W, Hu H, Chang R, Zhong J, Knabel M, O’Meally R, Cole RN, Pandey A, Semenza GL: Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell. 2011, 145: 732-744. 10.1016/j.cell.2011.03.054.PubMedPubMedCentral Luo W, Hu H, Chang R, Zhong J, Knabel M, O’Meally R, Cole RN, Pandey A, Semenza GL: Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell. 2011, 145: 732-744. 10.1016/j.cell.2011.03.054.PubMedPubMedCentral
94.
go back to reference Dombrauckas JD, Santarsiero BD, Mesecar AD: Structural basis for tumor pyruvate kinase M2 allosteric regulation and catalysis. Biochemistry. 2005, 44: 9417-9429. 10.1021/bi0474923.PubMed Dombrauckas JD, Santarsiero BD, Mesecar AD: Structural basis for tumor pyruvate kinase M2 allosteric regulation and catalysis. Biochemistry. 2005, 44: 9417-9429. 10.1021/bi0474923.PubMed
95.
go back to reference Vander Heiden MG, Locasale JW, Swanson KD, Sharfi H, Heffron GJ, Amador-Noguez D, Christofk HR, Wagner G, Rabinowitz JD, Asara JM, Cantley LC: Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science. 2010, 329: 1492-1499. 10.1126/science.1188015.PubMed Vander Heiden MG, Locasale JW, Swanson KD, Sharfi H, Heffron GJ, Amador-Noguez D, Christofk HR, Wagner G, Rabinowitz JD, Asara JM, Cantley LC: Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science. 2010, 329: 1492-1499. 10.1126/science.1188015.PubMed
96.
go back to reference Goldberg MS, Sharp PA: Pyruvate kinase M2-specific siRNA induces apoptosis and tumor regression. J Exp Med. 2012, 209: 217-224. 10.1084/jem.20111487.PubMedPubMedCentral Goldberg MS, Sharp PA: Pyruvate kinase M2-specific siRNA induces apoptosis and tumor regression. J Exp Med. 2012, 209: 217-224. 10.1084/jem.20111487.PubMedPubMedCentral
97.
go back to reference Cortes-Cros M, Hemmerlin C, Ferretti S, Zhang J, Gounarides JS, Yin H, Muller A, Haberkorn A, Chene P, Sellers WR, Hofmann F: M2 isoform of pyruvate kinase is dispensable for tumor maintenance and growth. Proc Natl Acad Sci U S A. 2013, 110: 489-494. 10.1073/pnas.1212780110.PubMedPubMedCentral Cortes-Cros M, Hemmerlin C, Ferretti S, Zhang J, Gounarides JS, Yin H, Muller A, Haberkorn A, Chene P, Sellers WR, Hofmann F: M2 isoform of pyruvate kinase is dispensable for tumor maintenance and growth. Proc Natl Acad Sci U S A. 2013, 110: 489-494. 10.1073/pnas.1212780110.PubMedPubMedCentral
98.
go back to reference Israelsen WJ, Dayton TL, Davidson SM, Fiske BP, Hosios AM, Bellinger G, Li J, Yu Y, Sasaki M, Horner JW, Burga LN, Xie J, Jurczak MJ, DePinho RA, Clish CB, Jacks T, Kibbey RG, Wulf GM, Di Vizio D, Mills GB, Cantley LC, Vander Heiden MG: PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell. 2013, 155: 397-409. 10.1016/j.cell.2013.09.025.PubMed Israelsen WJ, Dayton TL, Davidson SM, Fiske BP, Hosios AM, Bellinger G, Li J, Yu Y, Sasaki M, Horner JW, Burga LN, Xie J, Jurczak MJ, DePinho RA, Clish CB, Jacks T, Kibbey RG, Wulf GM, Di Vizio D, Mills GB, Cantley LC, Vander Heiden MG: PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell. 2013, 155: 397-409. 10.1016/j.cell.2013.09.025.PubMed
99.
go back to reference Seagroves TN, Ryan HE, Lu H, Wouters BG, Knapp M, Thibault P, Laderoute K, Johnson RS: Transcription factor HIF-1 is a necessary mediator of the Pasteur effect in mammalian cells. Mol Cell Biol. 2001, 21: 3436-3444. 10.1128/MCB.21.10.3436-3444.2001.PubMedPubMedCentral Seagroves TN, Ryan HE, Lu H, Wouters BG, Knapp M, Thibault P, Laderoute K, Johnson RS: Transcription factor HIF-1 is a necessary mediator of the Pasteur effect in mammalian cells. Mol Cell Biol. 2001, 21: 3436-3444. 10.1128/MCB.21.10.3436-3444.2001.PubMedPubMedCentral
100.
go back to reference Frezza C, Zheng L, Tennant DA, Papkovsky DB, Hedley BA, Kalna G, Watson DG, Gottlieb E: Metabolic profiling of hypoxic cells revealed a catabolic signature required for cell survival. PLoS One. 2011, 6: e24411-10.1371/journal.pone.0024411.PubMedPubMedCentral Frezza C, Zheng L, Tennant DA, Papkovsky DB, Hedley BA, Kalna G, Watson DG, Gottlieb E: Metabolic profiling of hypoxic cells revealed a catabolic signature required for cell survival. PLoS One. 2011, 6: e24411-10.1371/journal.pone.0024411.PubMedPubMedCentral
101.
go back to reference Golinska M, Troy H, Chung YL, McSheehy PM, Mayr M, Yin X, Ly L, Williams KJ, Airley RE, Harris AL, Latigo J, Perumal M, Aboagye EO, Perrett D, Stubbs M, Griffiths JR: Adaptation to HIF-1 deficiency by upregulation of the AMP/ATP ratio and phosphofructokinase activation in hepatomas. BMC Cancer. 2011, 11: 198-10.1186/1471-2407-11-198.PubMedPubMedCentral Golinska M, Troy H, Chung YL, McSheehy PM, Mayr M, Yin X, Ly L, Williams KJ, Airley RE, Harris AL, Latigo J, Perumal M, Aboagye EO, Perrett D, Stubbs M, Griffiths JR: Adaptation to HIF-1 deficiency by upregulation of the AMP/ATP ratio and phosphofructokinase activation in hepatomas. BMC Cancer. 2011, 11: 198-10.1186/1471-2407-11-198.PubMedPubMedCentral
102.
go back to reference Gao L, Mejias R, Echevarria M, Lopez-Barneo J: Induction of the glucose-6-phosphate dehydrogenase gene expression by chronic hypoxia in PC12 cells. FEBS Lett. 2004, 569: 256-260. 10.1016/j.febslet.2004.06.004.PubMed Gao L, Mejias R, Echevarria M, Lopez-Barneo J: Induction of the glucose-6-phosphate dehydrogenase gene expression by chronic hypoxia in PC12 cells. FEBS Lett. 2004, 569: 256-260. 10.1016/j.febslet.2004.06.004.PubMed
103.
go back to reference Pescador N, Villar D, Cifuentes D, Garcia-Rocha M, Ortiz-Barahona A, Vazquez S, Ordoñez A, Cuevas Y, Saez-Morales D, Garcia-Bermejo ML, Landazuri MO, Guinovart J, del Peso L: Hypoxia promotes glycogen accumulation through hypoxia inducible factor (HIF)-mediated induction of glycogen synthase 1. PLoS One. 2010, 5: e9644-10.1371/journal.pone.0009644.PubMedPubMedCentral Pescador N, Villar D, Cifuentes D, Garcia-Rocha M, Ortiz-Barahona A, Vazquez S, Ordoñez A, Cuevas Y, Saez-Morales D, Garcia-Bermejo ML, Landazuri MO, Guinovart J, del Peso L: Hypoxia promotes glycogen accumulation through hypoxia inducible factor (HIF)-mediated induction of glycogen synthase 1. PLoS One. 2010, 5: e9644-10.1371/journal.pone.0009644.PubMedPubMedCentral
104.
go back to reference Pelletier J, Bellot G, Gounon P, Lacas-Gervais S, Pouyssegur J, Mazure NM: Glycogen synthesis is induced in hypoxia by the hypoxia-inducible factor and promotes cancer cell survival. Front Oncol. 2012, 2: 18-PubMedPubMedCentral Pelletier J, Bellot G, Gounon P, Lacas-Gervais S, Pouyssegur J, Mazure NM: Glycogen synthesis is induced in hypoxia by the hypoxia-inducible factor and promotes cancer cell survival. Front Oncol. 2012, 2: 18-PubMedPubMedCentral
105.
go back to reference Favaro E, Bensaad K, Chong MG, Tennant DA, Ferguson DJ, Snell C, Steers G, Turley H, Li JL, Günther UL, Buffa FM, McIntyre A, Harris AL: Glucose utilization via glycogen phosphorylase sustains proliferation and prevents premature senescence in cancer cells. Cell Metab. 2012, 16: 751-764. 10.1016/j.cmet.2012.10.017.PubMed Favaro E, Bensaad K, Chong MG, Tennant DA, Ferguson DJ, Snell C, Steers G, Turley H, Li JL, Günther UL, Buffa FM, McIntyre A, Harris AL: Glucose utilization via glycogen phosphorylase sustains proliferation and prevents premature senescence in cancer cells. Cell Metab. 2012, 16: 751-764. 10.1016/j.cmet.2012.10.017.PubMed
106.
go back to reference Tun HW, Marlow LA, von Roemeling CA, Cooper SJ, Kreinest P, Wu K, Luxon BA, Sinha M, Anastasiadis PZ, Copland JA: Pathway signature and cellular differentiation in clear cell renal cell carcinoma. PLoS One. 2010, 5: e10696-10.1371/journal.pone.0010696.PubMedPubMedCentral Tun HW, Marlow LA, von Roemeling CA, Cooper SJ, Kreinest P, Wu K, Luxon BA, Sinha M, Anastasiadis PZ, Copland JA: Pathway signature and cellular differentiation in clear cell renal cell carcinoma. PLoS One. 2010, 5: e10696-10.1371/journal.pone.0010696.PubMedPubMedCentral
107.
go back to reference Kuhajda FP, Jenner K, Wood FD, Hennigar RA, Jacobs LB, Dick JD, Pasternack GR: Fatty acid synthesis: a potential selective target for antineoplastic therapy. Proc Natl Acad Sci U S A. 1994, 91: 6379-6383. 10.1073/pnas.91.14.6379.PubMedPubMedCentral Kuhajda FP, Jenner K, Wood FD, Hennigar RA, Jacobs LB, Dick JD, Pasternack GR: Fatty acid synthesis: a potential selective target for antineoplastic therapy. Proc Natl Acad Sci U S A. 1994, 91: 6379-6383. 10.1073/pnas.91.14.6379.PubMedPubMedCentral
108.
go back to reference Zhou W, Simpson PJ, McFadden JM, Townsend CA, Medghalchi SM, Vadlamudi A, Pinn ML, Ronnett GV, Kuhajda FP: Fatty acid synthase inhibition triggers apoptosis during S phase in human cancer cells. Cancer Res. 2003, 63: 7330-7337.PubMed Zhou W, Simpson PJ, McFadden JM, Townsend CA, Medghalchi SM, Vadlamudi A, Pinn ML, Ronnett GV, Kuhajda FP: Fatty acid synthase inhibition triggers apoptosis during S phase in human cancer cells. Cancer Res. 2003, 63: 7330-7337.PubMed
109.
go back to reference Bandyopadhyay S, Zhan R, Wang Y, Pai SK, Hirota S, Hosobe S, Takano Y, Saito K, Furuta E, Iiizumi M, Mohinta S, Watabe M, Chalfant C, Watabe K: Mechanism of apoptosis induced by the inhibition of fatty acid synthase in breast cancer cells. Cancer Res. 2006, 66: 5934-5940. 10.1158/0008-5472.CAN-05-3197.PubMed Bandyopadhyay S, Zhan R, Wang Y, Pai SK, Hirota S, Hosobe S, Takano Y, Saito K, Furuta E, Iiizumi M, Mohinta S, Watabe M, Chalfant C, Watabe K: Mechanism of apoptosis induced by the inhibition of fatty acid synthase in breast cancer cells. Cancer Res. 2006, 66: 5934-5940. 10.1158/0008-5472.CAN-05-3197.PubMed
110.
go back to reference Menendez JA, Lupu R: Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer. 2007, 7: 763-777. 10.1038/nrc2222.PubMed Menendez JA, Lupu R: Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer. 2007, 7: 763-777. 10.1038/nrc2222.PubMed
111.
go back to reference Ader I, Brizuela L, Bouquerel P, Malavaud B, Cuvillier O: Sphingosine kinase 1: a new modulator of hypoxia inducible factor 1alpha during hypoxia in human cancer cells. Cancer Res. 2008, 68: 8635-8642. 10.1158/0008-5472.CAN-08-0917.PubMed Ader I, Brizuela L, Bouquerel P, Malavaud B, Cuvillier O: Sphingosine kinase 1: a new modulator of hypoxia inducible factor 1alpha during hypoxia in human cancer cells. Cancer Res. 2008, 68: 8635-8642. 10.1158/0008-5472.CAN-08-0917.PubMed
112.
go back to reference Krishnamoorthy S, Jin R, Cai Y, Maddipati KR, Nie D, Pages G, Tucker SC, Honn KV: 12-Lipoxygenase and the regulation of hypoxia-inducible factor in prostate cancer cells. Exp Cell Res. 2010, 316: 1706-1715. 10.1016/j.yexcr.2010.03.005.PubMedPubMedCentral Krishnamoorthy S, Jin R, Cai Y, Maddipati KR, Nie D, Pages G, Tucker SC, Honn KV: 12-Lipoxygenase and the regulation of hypoxia-inducible factor in prostate cancer cells. Exp Cell Res. 2010, 316: 1706-1715. 10.1016/j.yexcr.2010.03.005.PubMedPubMedCentral
113.
go back to reference Furuta E, Pai SK, Zhan R, Bandyopadhyay S, Watabe M, Mo YY, Hirota S, Hosobe S, Tsukada T, Miura K, Kamada S, Saito K, Iiizumi M, Liu W, Ericsson J, Watabe K: Fatty acid synthase gene is up-regulated by hypoxia via activation of Akt and sterol regulatory element binding protein-1. Cancer Res. 2008, 68: 1003-1011. 10.1158/0008-5472.CAN-07-2489.PubMed Furuta E, Pai SK, Zhan R, Bandyopadhyay S, Watabe M, Mo YY, Hirota S, Hosobe S, Tsukada T, Miura K, Kamada S, Saito K, Iiizumi M, Liu W, Ericsson J, Watabe K: Fatty acid synthase gene is up-regulated by hypoxia via activation of Akt and sterol regulatory element binding protein-1. Cancer Res. 2008, 68: 1003-1011. 10.1158/0008-5472.CAN-07-2489.PubMed
114.
go back to reference Kaidi A, Qualtrough D, Williams AC, Paraskeva C: Direct transcriptional up-regulation of cyclooxygenase-2 by hypoxia-inducible factor (HIF)-1 promotes colorectal tumor cell survival and enhances HIF-1 transcriptional activity during hypoxia. Cancer Res. 2006, 66: 6683-6691. 10.1158/0008-5472.CAN-06-0425.PubMed Kaidi A, Qualtrough D, Williams AC, Paraskeva C: Direct transcriptional up-regulation of cyclooxygenase-2 by hypoxia-inducible factor (HIF)-1 promotes colorectal tumor cell survival and enhances HIF-1 transcriptional activity during hypoxia. Cancer Res. 2006, 66: 6683-6691. 10.1158/0008-5472.CAN-06-0425.PubMed
115.
go back to reference Gimm T, Wiese M, Teschemacher B, Deggerich A, Schödel J, Knaup KX, Hackenbeck T, Hellerbrand C, Amann K, Wiesener MS, Höning S, Eckardt KU, Warnecke C: Hypoxia-inducible protein 2 is a novel lipid droplet protein and a specific target gene of hypoxia-inducible factor-1. FASEB J. 2010, 24: 4443-4458. 10.1096/fj.10-159806.PubMed Gimm T, Wiese M, Teschemacher B, Deggerich A, Schödel J, Knaup KX, Hackenbeck T, Hellerbrand C, Amann K, Wiesener MS, Höning S, Eckardt KU, Warnecke C: Hypoxia-inducible protein 2 is a novel lipid droplet protein and a specific target gene of hypoxia-inducible factor-1. FASEB J. 2010, 24: 4443-4458. 10.1096/fj.10-159806.PubMed
116.
go back to reference Zhang Y, Wang H, Zhang J, Lv J, Huang Y: Positive feedback loop and synergistic effects between hypoxia-inducible factor-2alpha and stearoyl-CoA desaturase-1 promote tumorigenesis in clear cell renal cell carcinoma. Cancer Sci. 2013, 104: 416-422. 10.1111/cas.12108.PubMed Zhang Y, Wang H, Zhang J, Lv J, Huang Y: Positive feedback loop and synergistic effects between hypoxia-inducible factor-2alpha and stearoyl-CoA desaturase-1 promote tumorigenesis in clear cell renal cell carcinoma. Cancer Sci. 2013, 104: 416-422. 10.1111/cas.12108.PubMed
117.
go back to reference Krishnamoorthy S, Honn KV: Eicosanoids and other lipid mediators and the tumor hypoxic microenvironment. Cancer Metastasis Rev. 2011, 30: 613-618. 10.1007/s10555-011-9309-9.PubMed Krishnamoorthy S, Honn KV: Eicosanoids and other lipid mediators and the tumor hypoxic microenvironment. Cancer Metastasis Rev. 2011, 30: 613-618. 10.1007/s10555-011-9309-9.PubMed
118.
go back to reference Narravula S, Colgan SP: Hypoxia-inducible factor 1-mediated inhibition of peroxisome proliferator-activated receptor alpha expression during hypoxia. J Immunol. 2001, 166: 7543-7548.PubMed Narravula S, Colgan SP: Hypoxia-inducible factor 1-mediated inhibition of peroxisome proliferator-activated receptor alpha expression during hypoxia. J Immunol. 2001, 166: 7543-7548.PubMed
119.
go back to reference Yun Z, Maecker L, Johnson RS, Giaccia AJ: Inhibition of PPAR gamma 2 gene expression by the HIF-1-regulated gene DEC1/Stra 13: a mechanism for regulation of adipogenesis by hypoxia. Dev Cell. 2002, 2: 331-341. 10.1016/S1534-5807(02)00131-4.PubMed Yun Z, Maecker L, Johnson RS, Giaccia AJ: Inhibition of PPAR gamma 2 gene expression by the HIF-1-regulated gene DEC1/Stra 13: a mechanism for regulation of adipogenesis by hypoxia. Dev Cell. 2002, 2: 331-341. 10.1016/S1534-5807(02)00131-4.PubMed
120.
go back to reference Krishnan J, Suter M, Windak R, Krebs T, Felley A, Montessuit C, Tokarska-Schlattner M, Aasum E, Bogdanova A, Perriard E, Perriard JC, Larsen T, Pedrazzini T, Krek W: Activation of a HIF1alpha-PPARgamma axis underlies the integration of glycolytic and lipid anabolic pathways in pathologic cardiac hypertrophy. Cell Metab. 2009, 9: 512-524. 10.1016/j.cmet.2009.05.005.PubMed Krishnan J, Suter M, Windak R, Krebs T, Felley A, Montessuit C, Tokarska-Schlattner M, Aasum E, Bogdanova A, Perriard E, Perriard JC, Larsen T, Pedrazzini T, Krek W: Activation of a HIF1alpha-PPARgamma axis underlies the integration of glycolytic and lipid anabolic pathways in pathologic cardiac hypertrophy. Cell Metab. 2009, 9: 512-524. 10.1016/j.cmet.2009.05.005.PubMed
121.
go back to reference Wise DR, Ward PS, Shay JE, Cross JR, Gruber JJ, Sachdeva UM, Platt JM, DeMatteo RG, Simon MC, Thompson CB: Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of alpha-ketoglutarate to citrate to support cell growth and viability. Proc Natl Acad Sci U S A. 2011, 108: 19611-19616. 10.1073/pnas.1117773108.PubMedPubMedCentral Wise DR, Ward PS, Shay JE, Cross JR, Gruber JJ, Sachdeva UM, Platt JM, DeMatteo RG, Simon MC, Thompson CB: Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of alpha-ketoglutarate to citrate to support cell growth and viability. Proc Natl Acad Sci U S A. 2011, 108: 19611-19616. 10.1073/pnas.1117773108.PubMedPubMedCentral
122.
go back to reference Metallo CM, Gameiro PA, Bell EL, Mattaini KR, Yang J, Hiller K, Jewell CM, Johnson ZR, Irvine DJ, Guarente L, Kelleher JK, Vander Heiden MG, Iliopoulos O, Stephanopoulos G: Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature. 2011, 481: 380-384.PubMedPubMedCentral Metallo CM, Gameiro PA, Bell EL, Mattaini KR, Yang J, Hiller K, Jewell CM, Johnson ZR, Irvine DJ, Guarente L, Kelleher JK, Vander Heiden MG, Iliopoulos O, Stephanopoulos G: Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature. 2011, 481: 380-384.PubMedPubMedCentral
123.
go back to reference Mullen AR, Wheaton WW, Jin ES, Chen PH, Sullivan LB, Cheng T, Yang Y, Linehan WM, Chandel NS, DeBerardinis RJ: Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature. 2012, 481: 385-388.PubMedCentral Mullen AR, Wheaton WW, Jin ES, Chen PH, Sullivan LB, Cheng T, Yang Y, Linehan WM, Chandel NS, DeBerardinis RJ: Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature. 2012, 481: 385-388.PubMedCentral
124.
go back to reference Gameiro PA, Yang J, Metelo AM, Pérez-Carro R, Baker R, Wang Z, Arreola A, Rathmell WK, Olumi A, López-Larrubia P, Stephanopoulos G, Iliopoulos O: In vivo HIF-mediated reductive carboxylation is regulated by citrate levels and sensitizes VHL-deficient cells to glutamine deprivation. Cell Metab. 2013, 17: 372-385. 10.1016/j.cmet.2013.02.002.PubMedPubMedCentral Gameiro PA, Yang J, Metelo AM, Pérez-Carro R, Baker R, Wang Z, Arreola A, Rathmell WK, Olumi A, López-Larrubia P, Stephanopoulos G, Iliopoulos O: In vivo HIF-mediated reductive carboxylation is regulated by citrate levels and sensitizes VHL-deficient cells to glutamine deprivation. Cell Metab. 2013, 17: 372-385. 10.1016/j.cmet.2013.02.002.PubMedPubMedCentral
125.
go back to reference Kim JW, Tchernyshyov I, Semenza GL, Dang CV: HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006, 3: 177-185. 10.1016/j.cmet.2006.02.002.PubMed Kim JW, Tchernyshyov I, Semenza GL, Dang CV: HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006, 3: 177-185. 10.1016/j.cmet.2006.02.002.PubMed
126.
go back to reference Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC: HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 2006, 3: 187-197. 10.1016/j.cmet.2006.01.012.PubMed Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC: HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 2006, 3: 187-197. 10.1016/j.cmet.2006.01.012.PubMed
127.
go back to reference Tello D, Balsa E, Acosta-Iborra B, Fuertes-Yebra E, Elorza A, Ordóñez A, Corral-Escariz M, Soro I, López-Bernardo E, Perales-Clemente E, Martínez-Ruiz A, Enríquez JA, Aragonés J, Cadenas S, Landázuri MO: Induction of the mitochondrial NDUFA4L2 protein by HIF-1alpha decreases oxygen consumption by inhibiting Complex I activity. Cell Metab. 2011, 14: 768-779. 10.1016/j.cmet.2011.10.008.PubMed Tello D, Balsa E, Acosta-Iborra B, Fuertes-Yebra E, Elorza A, Ordóñez A, Corral-Escariz M, Soro I, López-Bernardo E, Perales-Clemente E, Martínez-Ruiz A, Enríquez JA, Aragonés J, Cadenas S, Landázuri MO: Induction of the mitochondrial NDUFA4L2 protein by HIF-1alpha decreases oxygen consumption by inhibiting Complex I activity. Cell Metab. 2011, 14: 768-779. 10.1016/j.cmet.2011.10.008.PubMed
128.
go back to reference Dahia PL, Ross KN, Wright ME, Hayashida CY, Santagata S, Barontini M, Kung AL, Sanso G, Powers JF, Tischler AS, Hodin R, Heitritter S, Moore F, Dluhy R, Sosa JA, Ocal IT, Benn DE, Marsh DJ, Robinson BG, Schneider K, Garber J, Arum SM, Korbonits M, Grossman A, Pigny P, Toledo SP, Nosé V, Li C, Stiles CD: A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet. 2005, 1: 72-80.PubMed Dahia PL, Ross KN, Wright ME, Hayashida CY, Santagata S, Barontini M, Kung AL, Sanso G, Powers JF, Tischler AS, Hodin R, Heitritter S, Moore F, Dluhy R, Sosa JA, Ocal IT, Benn DE, Marsh DJ, Robinson BG, Schneider K, Garber J, Arum SM, Korbonits M, Grossman A, Pigny P, Toledo SP, Nosé V, Li C, Stiles CD: A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet. 2005, 1: 72-80.PubMed
129.
go back to reference Fukuda R, Zhang H, Kim JW, Shimoda L, Dang CV, Semenza GL: HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell. 2007, 129: 111-122. 10.1016/j.cell.2007.01.047.PubMed Fukuda R, Zhang H, Kim JW, Shimoda L, Dang CV, Semenza GL: HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell. 2007, 129: 111-122. 10.1016/j.cell.2007.01.047.PubMed
130.
go back to reference Chan SY, Zhang YY, Hemann C, Mahoney CE, Zweier JL, Loscalzo J: MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2. Cell Metab. 2009, 10: 273-284. 10.1016/j.cmet.2009.08.015.PubMedPubMedCentral Chan SY, Zhang YY, Hemann C, Mahoney CE, Zweier JL, Loscalzo J: MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2. Cell Metab. 2009, 10: 273-284. 10.1016/j.cmet.2009.08.015.PubMedPubMedCentral
131.
go back to reference Favaro E, Ramachandran A, McCormick R, Gee H, Blancher C, Crosby M, Devlin C, Blick C, Buffa F, Li JL, Vojnovic B, Pires Das Neves R, Glazer P, Iborra F, Ivan M, Ragoussis J, Harris AL: MicroRNA-210 regulates mitochondrial free radical response to hypoxia and krebs cycle in cancer cells by targeting iron sulfur cluster protein ISCU. PLoS One. 2010, 5: e10345-10.1371/journal.pone.0010345.PubMedPubMedCentral Favaro E, Ramachandran A, McCormick R, Gee H, Blancher C, Crosby M, Devlin C, Blick C, Buffa F, Li JL, Vojnovic B, Pires Das Neves R, Glazer P, Iborra F, Ivan M, Ragoussis J, Harris AL: MicroRNA-210 regulates mitochondrial free radical response to hypoxia and krebs cycle in cancer cells by targeting iron sulfur cluster protein ISCU. PLoS One. 2010, 5: e10345-10.1371/journal.pone.0010345.PubMedPubMedCentral
132.
go back to reference Zhang H, Gao P, Fukuda R, Kumar G, Krishnamachary B, Zeller KI, Dang CV, Semenza GL: HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell. 2007, 11: 407-420. 10.1016/j.ccr.2007.04.001.PubMed Zhang H, Gao P, Fukuda R, Kumar G, Krishnamachary B, Zeller KI, Dang CV, Semenza GL: HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell. 2007, 11: 407-420. 10.1016/j.ccr.2007.04.001.PubMed
133.
go back to reference Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, Gonzalez FJ, Semenza GL: Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem. 2008, 283: 10892-10903. 10.1074/jbc.M800102200.PubMedPubMedCentral Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, Gonzalez FJ, Semenza GL: Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem. 2008, 283: 10892-10903. 10.1074/jbc.M800102200.PubMedPubMedCentral
134.
go back to reference Barthel A, Okino ST, Liao J, Nakatani K, Li J, Whitlock JP, Roth RA: Regulation of GLUT1 gene transcription by the serine/threonine kinase Akt1. J Biol Chem. 1999, 274: 20281-20286. 10.1074/jbc.274.29.20281.PubMed Barthel A, Okino ST, Liao J, Nakatani K, Li J, Whitlock JP, Roth RA: Regulation of GLUT1 gene transcription by the serine/threonine kinase Akt1. J Biol Chem. 1999, 274: 20281-20286. 10.1074/jbc.274.29.20281.PubMed
135.
go back to reference Calera MR, Martinez C, Liu H, Jack AK, Birnbaum MJ, Pilch PF: Insulin increases the association of Akt-2 with Glut4-containing vesicles. J Biol Chem. 1998, 273: 7201-7204. 10.1074/jbc.273.13.7201.PubMed Calera MR, Martinez C, Liu H, Jack AK, Birnbaum MJ, Pilch PF: Insulin increases the association of Akt-2 with Glut4-containing vesicles. J Biol Chem. 1998, 273: 7201-7204. 10.1074/jbc.273.13.7201.PubMed
136.
go back to reference Miinea CP, Sano H, Kane S, Sano E, Fukuda M, Peranen J, Lane WS, Lienhard GE: AS160, the Akt substrate regulating GLUT4 translocation, has a functional Rab GTPase-activating protein domain. Biochem J. 2005, 391: 87-93. 10.1042/BJ20050887.PubMedPubMedCentral Miinea CP, Sano H, Kane S, Sano E, Fukuda M, Peranen J, Lane WS, Lienhard GE: AS160, the Akt substrate regulating GLUT4 translocation, has a functional Rab GTPase-activating protein domain. Biochem J. 2005, 391: 87-93. 10.1042/BJ20050887.PubMedPubMedCentral
137.
go back to reference Novellasdemunt L, Tato I, Navarro-Sabate A, Ruiz-Meana M, Mendez-Lucas A, Perales JC, Garcia-Dorado D, Ventura F, Bartrons R, Rosa JL: Akt-dependent activation of the heart 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB2) isoenzyme by amino acids. J Biol Chem. 2013, 288: 10640-10651. 10.1074/jbc.M113.455998.PubMedPubMedCentral Novellasdemunt L, Tato I, Navarro-Sabate A, Ruiz-Meana M, Mendez-Lucas A, Perales JC, Garcia-Dorado D, Ventura F, Bartrons R, Rosa JL: Akt-dependent activation of the heart 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB2) isoenzyme by amino acids. J Biol Chem. 2013, 288: 10640-10651. 10.1074/jbc.M113.455998.PubMedPubMedCentral
138.
go back to reference Elstrom RL, Bauer DE, Buzzai M, Karnauskas R, Harris MH, Plas DR, Zhuang H, Cinalli RM, Alavi A, Rudin CM, Thompson CB: Akt stimulates aerobic glycolysis in cancer cells. Cancer Res. 2004, 64: 3892-3899. 10.1158/0008-5472.CAN-03-2904.PubMed Elstrom RL, Bauer DE, Buzzai M, Karnauskas R, Harris MH, Plas DR, Zhuang H, Cinalli RM, Alavi A, Rudin CM, Thompson CB: Akt stimulates aerobic glycolysis in cancer cells. Cancer Res. 2004, 64: 3892-3899. 10.1158/0008-5472.CAN-03-2904.PubMed
139.
go back to reference Robey RB, Hay N: Is Akt the “Warburg kinase”?-Akt-energy metabolism interactions and oncogenesis. Semin Cancer Biol. 2009, 19: 25-31. 10.1016/j.semcancer.2008.11.010.PubMedPubMedCentral Robey RB, Hay N: Is Akt the “Warburg kinase”?-Akt-energy metabolism interactions and oncogenesis. Semin Cancer Biol. 2009, 19: 25-31. 10.1016/j.semcancer.2008.11.010.PubMedPubMedCentral
140.
go back to reference Gordan JD, Thompson CB, Simon MC: HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. Cancer Cell. 2007, 12: 108-113. 10.1016/j.ccr.2007.07.006.PubMedPubMedCentral Gordan JD, Thompson CB, Simon MC: HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. Cancer Cell. 2007, 12: 108-113. 10.1016/j.ccr.2007.07.006.PubMedPubMedCentral
141.
go back to reference Dang CV, Kim JW, Gao P, Yustein J: The interplay between MYC and HIF in cancer. Nat Rev Cancer. 2008, 8: 51-56. 10.1038/nrc2274.PubMed Dang CV, Kim JW, Gao P, Yustein J: The interplay between MYC and HIF in cancer. Nat Rev Cancer. 2008, 8: 51-56. 10.1038/nrc2274.PubMed
142.
go back to reference Vander Heiden MG, Cantley LC, Thompson CB: Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009, 324: 1029-1033. 10.1126/science.1160809.PubMedPubMedCentral Vander Heiden MG, Cantley LC, Thompson CB: Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009, 324: 1029-1033. 10.1126/science.1160809.PubMedPubMedCentral
143.
go back to reference Shen C, Kaelin WG: The VHL/HIF axis in clear cell renal carcinoma. Semin Cancer Biol. 2013, 23: 18-25. 10.1016/j.semcancer.2012.06.001.PubMedPubMedCentral Shen C, Kaelin WG: The VHL/HIF axis in clear cell renal carcinoma. Semin Cancer Biol. 2013, 23: 18-25. 10.1016/j.semcancer.2012.06.001.PubMedPubMedCentral
144.
go back to reference Ratcliffe PJ: Oxygen sensing and hypoxia signalling pathways in animals: the implications of physiology for cancer. J Physiol. 2013, 591: 2027-2042.PubMedPubMedCentral Ratcliffe PJ: Oxygen sensing and hypoxia signalling pathways in animals: the implications of physiology for cancer. J Physiol. 2013, 591: 2027-2042.PubMedPubMedCentral
145.
go back to reference Hsu PP, Sabatini DM: Cancer cell metabolism: Warburg and beyond. Cell. 2008, 134: 703-707. 10.1016/j.cell.2008.08.021.PubMed Hsu PP, Sabatini DM: Cancer cell metabolism: Warburg and beyond. Cell. 2008, 134: 703-707. 10.1016/j.cell.2008.08.021.PubMed
146.
go back to reference Ward PS, Thompson CB: Metabolic reprogramming: a cancer hallmark even Warburg did not anticipate. Cancer Cell. 2012, 21: 297-308. 10.1016/j.ccr.2012.02.014.PubMedPubMedCentral Ward PS, Thompson CB: Metabolic reprogramming: a cancer hallmark even Warburg did not anticipate. Cancer Cell. 2012, 21: 297-308. 10.1016/j.ccr.2012.02.014.PubMedPubMedCentral
147.
go back to reference Losman JA, Kaelin WG: What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer. Genes Dev. 2013, 27: 836-852. 10.1101/gad.217406.113.PubMedPubMedCentral Losman JA, Kaelin WG: What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer. Genes Dev. 2013, 27: 836-852. 10.1101/gad.217406.113.PubMedPubMedCentral
148.
go back to reference Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL, Cantley LC: The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 2008, 452: 230-233. 10.1038/nature06734.PubMed Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL, Cantley LC: The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 2008, 452: 230-233. 10.1038/nature06734.PubMed
Metadata
Title
Hypoxia signaling pathways in cancer metabolism: the importance of co-selecting interconnected physiological pathways
Authors
Norma Masson
Peter J Ratcliffe
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Cancer & Metabolism / Issue 1/2014
Electronic ISSN: 2049-3002
DOI
https://doi.org/10.1186/2049-3002-2-3

Other articles of this Issue 1/2014

Cancer & Metabolism 1/2014 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine