title: Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis.
abstract: 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 1alpha (HIF-1alpha). In human gliomas and other cancer cell lines, the accumulation of HIF-1alpha protein under aerobic conditions requires the metabolism of glucose to pyruvate that prevents the aerobic degradation of HIF-1alpha 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.
authors.affiliation: Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, USA.
authors.forename: Huasheng
authors.initials: H
authors.lastname: Lu
authors.forename: Robert A
authors.initials: RA
authors.lastname: Forbes
authors.forename: Ajay
authors.initials: A
authors.lastname: Verma
mesh_terms: D000332:Aerobiosis; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009369:Neoplasms / Q000378:metabolism*; D019289:Pyruvic Acid / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D019289:Pyruvic Acid; D004247:DNA; D005947:Glucose