Hypoxia-inducible Factor 1 Activation by Aerobic Glycolysis Implicates the Warburg Effect in Carcinogenesis

Cancer cells display high rates of aerobic glycolysis, a phenomenon known historically as the Warburg effect. Lactate and pyruvate, the end products of glycolysis, are highly produced by cancer cells even in the presence of oxygen. Hypoxia-induced gene expression in cancer cells has been linked to malignant transformation. Here we provide evidence that lactate and pyruvate regulate hypoxia-inducible gene expression independently of hypoxia by stimulating the accumulation of hypoxia-inducible Factor 1α (HIF-1α). In human gliomas and other cancer cell lines, the accumulation of HIF-1α protein under aerobic conditions requires the metabolism of glucose to pyruvate that prevents the aerobic degradation of HIF-1α protein, activates HIF-1 DNA binding activity, and enhances the expression of several HIF-1-activated genes including erythropoietin, vascular endothelial growth factor, glucose transporter 3, and aldolase A. Our findings support a novel role for pyruvate in metabolic signaling and suggest a mechanism by which high rates of aerobic glycolysis can promote the malignant transformation and survival of cancer cells. Cancer cells display high rates of aerobic glycolysis, a phenomenon known historically as the Warburg effect. Lactate and pyruvate, the end products of glycolysis, are highly produced by cancer cells even in the presence of oxygen. Hypoxia-induced gene expression in cancer cells has been linked to malignant transformation. Here we provide evidence that lactate and pyruvate regulate hypoxia-inducible gene expression independently of hypoxia by stimulating the accumulation of hypoxia-inducible Factor 1α (HIF-1α). In human gliomas and other cancer cell lines, the accumulation of HIF-1α protein under aerobic conditions requires the metabolism of glucose to pyruvate that prevents the aerobic degradation of HIF-1α protein, activates HIF-1 DNA binding activity, and enhances the expression of several HIF-1-activated genes including erythropoietin, vascular endothelial growth factor, glucose transporter 3, and aldolase A. Our findings support a novel role for pyruvate in metabolic signaling and suggest a mechanism by which high rates of aerobic glycolysis can promote the malignant transformation and survival of cancer cells. hypoxia-inducible Factor 1α/β vascular endothelial growth factor erythropoietin glucose transporters HIF-prolyl hydroxylases desferrioxamine minimum Eagle's medium reverse transcriptase iodoacetate lactate dehydrogenase α-cyano-4-hydroxycinnamate 2-oxoglutarate glucose glyceraldehyde dehydrogenase Cancer cell energy metabolism deviates significantly from that of normal tissues. Cancer cells maintain high aerobic glycolytic rates and produce high levels of lactate and pyruvate (1Galarraga J. Loreck D.J. Graham J.F. DeLaPaz R.L. Smith B.H. Hallgren D. Cummins C.J. Metab. Brain Dis. 1986; 1: 279-291Crossref PubMed Scopus (38) Google Scholar). This phenomenon was first described in cancer more than seven decades ago and is known historically as the Warburg effect (2Warburg O. Science. 1956; 123: 309-314Crossref PubMed Scopus (9333) Google Scholar, 3Semenza G.L. Crit. Rev. Biochem. Mol. Biol. 2000; 35: 71-103Crossref PubMed Scopus (555) Google Scholar). Preferential reliance on glycolysis is correlated with disease progression in several types of cancers (4Schwickert G. Walenta S. Sundfor K. Rofstad E.K. Mueller-Klieser W. Cancer Res. 1995; 55: 4757-4759PubMed Google Scholar, 5Walenta S. Salameh A. Lyng H. Evensen J.F. Mitze M. Rofstad E.K. Mueller-Klieser W. Am. J. Pathol. 1997; 150: 409-415PubMed Google Scholar), and the activities of hexokinase, phosphofructokinase, and pyruvate kinase are consistently and significantly increased in cancer cells (6Dominguez J.E. Graham J.F. Cummins C.J. Loreck D.J. Galarraga J. Vander Feen J. DeLaPaz R. Smith B.H. Metab. Brain Dis. 1987; 2: 17-30Crossref PubMed Scopus (25) Google Scholar, 7Van Veelen C.W. Rijksen G. Van Ketel B.A. Staal G.E. Br. J. Neurosurg. 1988; 2: 257-263Crossref PubMed Scopus (12) Google Scholar, 8Dang C.V. Semenza G.L. Trends Biochem. Sci. 1999; 24: 68-72Abstract Full Text Full Text PDF PubMed Scopus (923) Google Scholar). Although oncogenes such as ras, src, and myc have been found to enhance aerobic glycolysis by increasing the expression of glucose transporters and glycolytic enzymes (8Dang C.V. Semenza G.L. Trends Biochem. Sci. 1999; 24: 68-72Abstract Full Text Full Text PDF PubMed Scopus (923) Google Scholar, 9Flier J.S. Mueckler M.M. Usher P. Lodish H.F. Science. 1987; 235: 1492-1495Crossref PubMed Scopus (685) Google Scholar, 10Osthus R.C. Shim H., Li, Q. Reddy R. Mukherjee M., Xu, Y. Wonsey D. Lee L.A. Dang C.V. J. Biol. Chem. 2000; 275: 21797-21800Abstract Full Text Full Text PDF PubMed Scopus (607) Google Scholar), the relevance of the Warburg effect to cancer cell biology has remained obscure. Hypoxia is another common feature of many solid cancers and has been linked to malignant transformation, metastasis, and treatment resistance (11Hockel M. Vaupel P. J. Natl. Cancer Inst. 2001; 93: 266-276Crossref PubMed Scopus (2131) Google Scholar). The adaptation of cancer cells to hypoxia is mediated via hypoxia-inducible Factor 1 (HIF-1),1 a key transcription factor that up-regulates a series of genes involved in glycolytic energy metabolism, angiogenesis, cell survival, and erythropoiesis. Included among these genes are vascular endothelial growth factor (VEGF), erythropoietin (EPO), glucose transporters (GLUT), and several glycolytic enzymes (12Maxwell P.H. Pugh C.W. Ratcliffe P.J. Curr. Opin. Genet. Dev. 2001; 11: 293-299Crossref PubMed Scopus (332) Google Scholar, 13Semenza G.L. J. Appl. Physiol. 2000; 88: 1474-1480Crossref PubMed Scopus (1470) Google Scholar).HIF-1 is a heterodimer composed of two subunits, HIF-1α and HIF-1β (14Wang G.L. Semenza G.L. J. Biol. Chem. 1995; 270: 1230-1237Abstract Full Text Full Text PDF PubMed Scopus (1694) Google Scholar), both of which are constitutively expressed in mammalian cells. The regulation of the HIF-1 complex is mainly dependent on the degradation of the HIF-1α subunit. Under nonhypoxic conditions, HIF-1α undergoes ubiquination and proteasomal degradation (15Huang L.E., Gu, J. Schau M. Bunn H.F. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 7987-7992Crossref PubMed Scopus (1832) Google Scholar, 16Kallio P.J. Wilson W., J. O'Brien S. Makino Y. Poellinger L. J. Biol. Chem. 1999; 274: 6519-6525Abstract Full Text Full Text PDF PubMed Scopus (685) Google Scholar). This process involves the binding of the von Hippel-Lindau tumor suppressor protein to an oxygen-dependent degradation domain on the HIF-1α protein. A family of prolyl hydroxylase enzymes regulates the binding of von Hippel-Lindau tumor suppressor protein to HIF-1α by hydroxylating key proline residues on the HIF-1α protein (17Jaakkola P. Mole D.R. Tian Y-M. Wilson M.I. Gielbert J. Gaskell S.J. von Kriegsheim A. Hebestreit H.F. Mukherji M. Schofield C.J. Maxwell P.H. Pugh C.W. Ratcliffe P.J. Science. 2001; 292: 468-472Crossref PubMed Scopus (4370) Google Scholar, 18Ivan M. Kondo K. Yang H. Kim W. Valiando J. Ohh M. Salic A. Asara J.M. Lane W.S. Kaelin W.G., Jr. Science. 2001; 292: 464-468Crossref PubMed Scopus (3828) Google Scholar, 19Epstein A.C.R. Gleadle J.M. McNeill L.A. Hewitson K.S. O'Rourke J. Mole D.R. Mukherji M. Metzen E. Wilson M.I. Dhanda A. Tian Y-M. Masson N. Hamilton D.L. Jaakkola P. Barstead R. Hodgkin J. Maxwell P.H. Pugh C.W. Schofield C.J. Ratcliffe P.J. Cell. 2001; 107: 43-54Abstract Full Text Full Text PDF PubMed Scopus (2697) Google Scholar, 20Bruick R.K. McKnight S.L. Science. 2001; 294: 1337-1340Crossref PubMed Scopus (2088) Google Scholar). Oxygen and iron are required for the activity of these HIF prolyl hydroxylases (HIF-PH), thus explaining why HIF-1α protein accumulates during hypoxia as well as in the presence of the iron chelator desferrioxamine (DFO) or iron-displacing metals like cobalt. Although hypoxia is the ubiquitous inducer of HIF-1α in all cells tested, other stimuli such as insulin, insulin-like growth factor 1, growth factor, and can HIF-1α levels in several cell types E. Y. M. J. 1988; Scopus Google Scholar, H. K. D. E. M.M. Semenza G.L. Cancer Res. 2000; Google Scholar, E. J. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Google Scholar). the of HIF-1 by these has to is highly with cancer cell growth and survival, tumor tumor angiogenesis, and H., E. M. D. P. Semenza G.L. Cancer Res. 1999; Google Scholar, P. M. A. G. G. Cancer Res. 2000; Google Scholar, N. M. A. J. J. H. K. M. M. Cancer Res. 2001; Google Scholar, S. J.M. Kaelin W.G., Jr. 2000; PubMed Scopus Google Scholar). In HIF-1α expression has been in of the and and in the normal H., E. M. D. P. Semenza G.L. Cancer Res. 1999; Google Scholar). In HIF-1α expression correlated with D. H. J.M. E. Semenza G.L. 2000; 88: PubMed Scopus Google Scholar). The expression of another gene as well as the is increased in gliomas and cancers G. P. R.L. E. K. A. Cancer Res. 2001; Google Scholar). Although hypoxia is to the to HIF-1α HIF-1α expression has been in several nonhypoxic cancer cell N. M. A. J. J. H. K. M. M. Cancer Res. 2001; Google and normal M. D. J. 2001; PubMed Scopus Google Scholar). with the regulation of HIF-1α by other than hypoxia E. Y. M. J. 1988; Scopus Google Scholar, H. K. D. E. M.M. Semenza G.L. Cancer Res. 2000; Google Scholar, E. J. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Google suggest a role for signaling in HIF-1 Here we that in human cancer as well as in normal the of medium with or pyruvate HIF-1α protein levels and activates gene that the of gene expression is a of aerobic This cell survival and promote the progression of cancers that on aerobic is that end products of glycolytic metabolism can promote HIF-1α protein and gene Our findings suggest that the expression of HIF-1α protein in significantly by the cell medium as well as by metabolic The mechanism of HIF-1α by glucose metabolism to from that of hypoxia or these can HIF-1α in the of glucose and The effect of glucose was by by 1 a key role for glycolytic end metabolism to dehydrogenase to pyruvate in cells with pyruvate pyruvate is by is by lactate in all cells or in cells. pyruvate and lactate HIF-1α protein accumulation for the and effect 1 in the to a role in HIF-1α and Although both lactate and pyruvate in cancer cells and HIF-1α protein accumulation and lactate to to pyruvate for effect to a novel of of pyruvate in HIF-1α protein to in a to hypoxia or in that HIF-1α degradation The degradation of HIF-1α is via the oxygen-dependent of key proline residues in the HIF-1α oxygen-dependent degradation This is mediated by a family of that and for is that pyruvate 2-oxoglutarate from and thus activity in a to the of iron by cobalt. we to reverse the accumulation of HIF-1α by pyruvate in or in cells with of 2-oxoglutarate In and effect on HIF-1α accumulation is a to the levels of required for a with to that of pyruvate Mol. Cell. Biochem. 1997; PubMed Scopus Google Scholar), HIF-1α levels and lactate to activity in a to the mechanism HIF-1α accumulation by pyruvate suggest a of pyruvate the HIF-1α proline von Hippel-Lindau tumor suppressor or that pyruvate enhance gene expression is with the of pyruvate in and in M. E. Lee S. Kim Kim K. Kim Y. Cancer Res. 2001; Google Scholar). In cancer glycolysis is for energy even in the presence of oxygen. This aerobic glycolysis of cancer cells known as the Warburg effect in to progression and malignant transformation by the expression of many genes for glycolytic glucose and glucose are by hypoxia G.L. Crit. Rev. Biochem. Mol. Biol. 2000; 35: 71-103Crossref PubMed Scopus (555) Google Scholar, 8Dang C.V. Semenza G.L. Trends Biochem. Sci. 1999; 24: 68-72Abstract Full Text Full Text PDF PubMed Scopus (923) Google Scholar, L. M. M. G. G. 1999; PubMed Scopus Google Scholar), the Warburg effect a mechanism to maintain the expression of genes on by to the of HIF-1 by several and E. Y. M. J. 1988; Scopus Google Scholar, H. K. D. E. M.M. Semenza G.L. Cancer Res. 2000; Google Scholar, E. J. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Google Scholar). and activities are of many cancer and activity is by insulin, insulin-like growth and growth factor D. G. Semenza G. Cancer Res. 1999; Google Scholar), all of which can HIF-1 under an mechanism the signaling L. M. M. G. G. 1999; PubMed Scopus Google Scholar, D. G. Semenza G. Cancer Res. 1999; Google Scholar). to HIF-1 H., E. M. D. P. Semenza G.L. Cancer Res. 1999; Google Scholar), the activity of pyruvate kinase with malignant progression in cancer M. PubMed Scopus Google Scholar). Cancer cells display pyruvate G. G. S. Cancer Res. Google Scholar), and a to promote of HIF-1 D. E. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar), is well known to promote pyruvate by pyruvate several HIF-1 via of glycolysis or via of pyruvate findings have The of gene expression has as a for cancer treatment J. 2001; Google Scholar). Our suggest that aerobic glycolysis in from gene expression is in many including vascular and high G.L. Trends Mol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). The of in from are to gene expression M. Semenza G.L. 2000; PubMed Scopus Google Scholar). Our findings suggest that pyruvate as a and in these Cancer cell energy metabolism deviates significantly from that of normal tissues. Cancer cells maintain high aerobic glycolytic rates and produce high levels of lactate and pyruvate (1Galarraga J. Loreck D.J. Graham J.F. DeLaPaz R.L. Smith B.H. Hallgren D. Cummins C.J. Metab. Brain Dis. 1986; 1: 279-291Crossref PubMed Scopus (38) Google Scholar). This phenomenon was first described in cancer more than seven decades ago and is known historically as the Warburg effect (2Warburg O. Science. 1956; 123: 309-314Crossref PubMed Scopus (9333) Google Scholar, 3Semenza G.L. Crit. Rev. Biochem. Mol. Biol. 2000; 35: 71-103Crossref PubMed Scopus (555) Google Scholar). Preferential reliance on glycolysis is correlated with disease progression in several types of cancers (4Schwickert G. Walenta S. Sundfor K. Rofstad E.K. Mueller-Klieser W. Cancer Res. 1995; 55: 4757-4759PubMed Google Scholar, 5Walenta S. Salameh A. Lyng H. Evensen J.F. Mitze M. Rofstad E.K. Mueller-Klieser W. Am. J. Pathol. 1997; 150: 409-415PubMed Google Scholar), and the activities of hexokinase, phosphofructokinase, and pyruvate kinase are consistently and significantly increased in cancer cells (6Dominguez J.E. Graham J.F. Cummins C.J. Loreck D.J. Galarraga J. Vander Feen J. DeLaPaz R. Smith B.H. Metab. Brain Dis. 1987; 2: 17-30Crossref PubMed Scopus (25) Google Scholar, 7Van Veelen C.W. Rijksen G. Van Ketel B.A. Staal G.E. Br. J. Neurosurg. 1988; 2: 257-263Crossref PubMed Scopus (12) Google Scholar, 8Dang C.V. Semenza G.L. Trends Biochem. Sci. 1999; 24: 68-72Abstract Full Text Full Text PDF PubMed Scopus (923) Google Scholar). Although oncogenes such as ras, src, and myc have been found to enhance aerobic glycolysis by increasing the expression of glucose transporters and glycolytic enzymes (8Dang C.V. Semenza G.L. Trends Biochem. Sci. 1999; 24: 68-72Abstract Full Text Full Text PDF PubMed Scopus (923) Google Scholar, 9Flier J.S. Mueckler M.M. Usher P. Lodish H.F. Science. 1987; 235: 1492-1495Crossref PubMed Scopus (685) Google Scholar, 10Osthus R.C. Shim H., Li, Q. Reddy R. Mukherjee M., Xu, Y. Wonsey D. Lee L.A. Dang C.V. J. Biol. Chem. 2000; 275: 21797-21800Abstract Full Text Full Text PDF PubMed Scopus (607) Google Scholar), the relevance of the Warburg effect to cancer cell biology has remained obscure. Hypoxia is another common feature of many solid cancers and has been linked to malignant transformation, metastasis, and treatment resistance (11Hockel M. Vaupel P. J. Natl. Cancer Inst. 2001; 93: 266-276Crossref PubMed Scopus (2131) Google Scholar). The adaptation of cancer cells to hypoxia is mediated via hypoxia-inducible Factor 1 (HIF-1),1 a key transcription factor that up-regulates a series of genes involved in glycolytic energy metabolism, angiogenesis, cell survival, and erythropoiesis. Included among these genes are vascular endothelial growth factor (VEGF), erythropoietin (EPO), glucose transporters (GLUT), and several glycolytic enzymes (12Maxwell P.H. Pugh C.W. Ratcliffe P.J. Curr. Opin. Genet. Dev. 2001; 11: 293-299Crossref PubMed Scopus (332) Google Scholar, 13Semenza G.L. J. Appl. Physiol. 2000; 88: 1474-1480Crossref PubMed Scopus (1470) Google Scholar). HIF-1 is a heterodimer composed of two subunits, HIF-1α and HIF-1β (14Wang G.L. Semenza G.L. J. Biol. Chem. 1995; 270: 1230-1237Abstract Full Text Full Text PDF PubMed Scopus (1694) Google Scholar), both of which are constitutively expressed in mammalian cells. The regulation of the HIF-1 complex is mainly dependent on the degradation of the HIF-1α subunit. Under nonhypoxic conditions, HIF-1α undergoes ubiquination and proteasomal degradation (15Huang L.E., Gu, J. Schau M. Bunn H.F. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 7987-7992Crossref PubMed Scopus (1832) Google Scholar, 16Kallio P.J. Wilson W., J. O'Brien S. Makino Y. Poellinger L. J. Biol. Chem. 1999; 274: 6519-6525Abstract Full Text Full Text PDF PubMed Scopus (685) Google Scholar). This process involves the binding of the von Hippel-Lindau tumor suppressor protein to an oxygen-dependent degradation domain on the HIF-1α protein. A family of prolyl hydroxylase enzymes regulates the binding of von Hippel-Lindau tumor suppressor protein to HIF-1α by hydroxylating key proline residues on the HIF-1α protein (17Jaakkola P. Mole D.R. Tian Y-M. Wilson M.I. Gielbert J. Gaskell S.J. von Kriegsheim A. Hebestreit H.F. Mukherji M. Schofield C.J. Maxwell P.H. Pugh C.W. Ratcliffe P.J. Science. 2001; 292: 468-472Crossref PubMed Scopus (4370) Google Scholar, 18Ivan M. Kondo K. Yang H. Kim W. Valiando J. Ohh M. Salic A. Asara J.M. Lane W.S. Kaelin W.G., Jr. Science. 2001; 292: 464-468Crossref PubMed Scopus (3828) Google Scholar, 19Epstein A.C.R. Gleadle J.M. McNeill L.A. Hewitson K.S. O'Rourke J. Mole D.R. Mukherji M. Metzen E. Wilson M.I. Dhanda A. Tian Y-M. Masson N. Hamilton D.L. Jaakkola P. Barstead R. Hodgkin J. Maxwell P.H. Pugh C.W. Schofield C.J. Ratcliffe P.J. Cell. 2001; 107: 43-54Abstract Full Text Full Text PDF PubMed Scopus (2697) Google Scholar, 20Bruick R.K. McKnight S.L. Science. 2001; 294: 1337-1340Crossref PubMed Scopus (2088) Google Scholar). Oxygen and iron are required for the activity of these HIF prolyl hydroxylases (HIF-PH), thus explaining why HIF-1α protein accumulates during hypoxia as well as in the presence of the iron chelator desferrioxamine (DFO) or iron-displacing metals like cobalt. Although hypoxia is the ubiquitous inducer of HIF-1α in all cells tested, other stimuli such as insulin, insulin-like growth factor 1, growth factor, and can HIF-1α levels in several cell types E. Y. M. J. 1988; Scopus Google Scholar, H. K. D. E. M.M. Semenza G.L. Cancer Res. 2000; Google Scholar, E. J. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Google Scholar). the of HIF-1 by these has to HIF-1 is highly with cancer cell growth and survival, tumor tumor angiogenesis, and H., E. M. D. P. Semenza G.L. Cancer Res. 1999; Google Scholar, P. M. A. G. G. Cancer Res. 2000; Google Scholar, N. M. A. J. J. H. K. M. M. Cancer Res. 2001; Google Scholar, S. J.M. Kaelin W.G., Jr. 2000; PubMed Scopus Google Scholar). In HIF-1α expression has been in of the and and in the normal H., E. M. D. P. Semenza G.L. Cancer Res. 1999; Google Scholar). In HIF-1α expression correlated with D. H. J.M. E. Semenza G.L. 2000; 88: PubMed Scopus Google Scholar). The expression of another gene as well as the is increased in gliomas and cancers G. P. R.L. E. K. A. Cancer Res. 2001; Google Scholar). Although hypoxia is to the to HIF-1α HIF-1α expression has been in several nonhypoxic cancer cell N. M. A. J. J. H. K. M. M. Cancer Res. 2001; Google and normal M. D. J. 2001; PubMed Scopus Google Scholar). with the regulation of HIF-1α by other than hypoxia E. Y. M. J. 1988; Scopus Google Scholar, H. K. D. E. M.M. Semenza G.L. Cancer Res. 2000; Google Scholar, E. J. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Google suggest a role for signaling in HIF-1 Here we that in human cancer as well as in normal the of medium with or pyruvate HIF-1α protein levels and activates gene that the of gene expression is a of aerobic This cell survival and promote the progression of cancers that on aerobic is that end products of glycolytic metabolism can promote HIF-1α protein and gene Our findings suggest that the expression of HIF-1α protein in significantly by the cell medium as well as by metabolic The mechanism of HIF-1α by glucose metabolism to from that of hypoxia or these can HIF-1α in the of glucose and The effect of glucose was by by 1 a key role for glycolytic end metabolism to dehydrogenase to pyruvate in cells with pyruvate pyruvate is by is by lactate in all cells or in cells. pyruvate and lactate HIF-1α protein accumulation for the and effect 1 in the to a role in HIF-1α and Although both lactate and pyruvate in cancer cells and HIF-1α protein accumulation and lactate to to pyruvate for effect to a novel of of pyruvate in HIF-1α protein to in a to hypoxia or in that HIF-1α degradation The degradation of HIF-1α is via the oxygen-dependent of key proline residues in the HIF-1α oxygen-dependent degradation This is mediated by a family of that and for is that pyruvate 2-oxoglutarate from and thus activity in a to the of iron by cobalt. we to reverse the accumulation of HIF-1α by pyruvate in or in cells with of 2-oxoglutarate In and effect on HIF-1α accumulation is a to the levels of required for a with to that of pyruvate Mol. Cell. Biochem. 1997; PubMed Scopus Google Scholar), HIF-1α levels and lactate to activity in a to the mechanism HIF-1α accumulation by pyruvate suggest a of pyruvate the HIF-1α proline von Hippel-Lindau tumor suppressor or that pyruvate enhance gene expression is with the of pyruvate in and in M. E. Lee S. Kim Kim K. Kim Y. Cancer Res. 2001; Google Scholar). In cancer glycolysis is for energy even in the presence of oxygen. This aerobic glycolysis of cancer cells known as the Warburg effect in to progression and malignant transformation by the expression of many genes for glycolytic glucose and glucose are by hypoxia G.L. Crit. Rev. Biochem. Mol. Biol. 2000; 35: 71-103Crossref PubMed Scopus (555) Google Scholar, 8Dang C.V. Semenza G.L. Trends Biochem. Sci. 1999; 24: 68-72Abstract Full Text Full Text PDF PubMed Scopus (923) Google Scholar, L. M. M. G. G. 1999; PubMed Scopus Google Scholar), the Warburg effect a mechanism to maintain the expression of genes on by to the of HIF-1 by several and E. Y. M. J. 1988; Scopus Google Scholar, H. K. D. E. M.M. Semenza G.L. Cancer Res. 2000; Google Scholar, E. J. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Google Scholar). and activities are of many cancer and activity is by insulin, insulin-like growth and growth factor D. G. Semenza G. Cancer Res. 1999; Google Scholar), all of which can HIF-1 under an mechanism the signaling L. M. M. G. G. 1999; PubMed Scopus Google Scholar, D. G. Semenza G. Cancer Res. 1999; Google Scholar). to HIF-1 H., E. M. D. P. Semenza G.L. Cancer Res. 1999; Google Scholar), the activity of pyruvate kinase with malignant progression in cancer M. PubMed Scopus Google Scholar). Cancer cells display pyruvate G. G. S. Cancer Res. Google Scholar), and a to promote of HIF-1 D. E. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar), is well known to promote pyruvate by pyruvate several HIF-1 via of glycolysis or via of pyruvate findings have The of gene expression has as a for cancer treatment J. 2001; Google Scholar). Our suggest that aerobic glycolysis in from gene expression is in many including vascular and high G.L. Trends Mol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). The of in from are to gene expression M. Semenza G.L. 2000; PubMed Scopus Google Scholar). Our findings suggest that pyruvate as a and in these The is that end products of glycolytic metabolism can promote HIF-1α protein and gene Our findings suggest that the expression of HIF-1α protein in significantly by the cell medium as well as by metabolic The mechanism of HIF-1α by glucose metabolism to from that of hypoxia or these can HIF-1α in the of glucose and The effect of glucose was by by 1 a key role for glycolytic end metabolism to dehydrogenase to pyruvate in cells with pyruvate pyruvate is by is by lactate in all cells or in cells. pyruvate and lactate HIF-1α protein accumulation for the and effect 1 in the to a role in HIF-1α and Although both lactate and pyruvate in cancer cells and HIF-1α protein accumulation and lactate to to pyruvate for effect to a novel of of pyruvate in HIF-1α protein to in a to hypoxia or in that HIF-1α degradation The degradation of HIF-1α is via the oxygen-dependent of key proline residues in the HIF-1α oxygen-dependent degradation This is mediated by a family of that and for is that pyruvate 2-oxoglutarate from and thus activity in a to the of iron by cobalt. we to reverse the accumulation of HIF-1α by pyruvate in or in cells with of 2-oxoglutarate In and effect on HIF-1α accumulation is a to the levels of required for a with to that of pyruvate Mol. Cell. Biochem. 1997; PubMed Scopus Google Scholar), HIF-1α levels and lactate to activity in a to the mechanism HIF-1α accumulation by pyruvate suggest a of pyruvate the HIF-1α proline von Hippel-Lindau tumor suppressor or The that pyruvate enhance gene expression is with the of pyruvate in and in M. E. Lee S. Kim Kim K. Kim Y. Cancer Res. 2001; Google Scholar). In cancer glycolysis is for energy even in the presence of oxygen. This aerobic glycolysis of cancer cells known as the Warburg effect in to progression and malignant transformation by the expression of many genes for glycolytic glucose and glucose are by hypoxia G.L. Crit. Rev. Biochem. Mol. Biol. 2000; 35: 71-103Crossref PubMed Scopus (555) Google Scholar, 8Dang C.V. Semenza G.L. Trends Biochem. Sci. 1999; 24: 68-72Abstract Full Text Full Text PDF PubMed Scopus (923) Google Scholar, L. M. M. G. G. 1999; PubMed Scopus Google Scholar), the Warburg effect a mechanism to maintain the expression of genes on by to the of HIF-1 by several and E. Y. M. J. 1988; Scopus Google Scholar, H. K. D. E. M.M. Semenza G.L. Cancer Res. 2000; Google Scholar, E. J. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Google Scholar). and activities are of many cancer and activity is by insulin, insulin-like growth and growth factor D. G. Semenza G. Cancer Res. 1999; Google Scholar), all of which can HIF-1 under an mechanism the signaling L. M. M. G. G. 1999; PubMed Scopus Google Scholar, D. G. Semenza G. Cancer Res. 1999; Google Scholar). to HIF-1 H., E. M. D. P. Semenza G.L. Cancer Res. 1999; Google Scholar), the activity of pyruvate kinase with malignant progression in cancer M. PubMed Scopus Google Scholar). Cancer cells display pyruvate G. G. S. Cancer Res. Google Scholar), and a to promote of HIF-1 D. E. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar), is well known to promote pyruvate by pyruvate several HIF-1 via of glycolysis or via of pyruvate Our findings have The of gene expression has as a for cancer treatment J. 2001; Google Scholar). Our suggest that aerobic glycolysis in from gene expression is in many including vascular and high G.L. Trends Mol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). The of in from are to gene expression M. Semenza G.L. 2000; PubMed Scopus Google Scholar). Our findings suggest that pyruvate as a and in these