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Papers In Press, published online ahead of print April 9, 2002
J. Biol. Chem, 10.1074/jbc.M202487200
Submitted on March 14, 2002
Revised on April 9, 2002
Accepted on April 9, 2002

Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis

Husheng Lu, Robert A. Forbes, and Ajay Verma

Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814

Corresponding Author: averma{at}usuhs.mil

Cancer cells display high rates of aerobic glycolysis, a phenomenon known historically as the Warburg effect. Lactate and pyruvate, the endproducts 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 1 alpha1 (HIF-1a). In human gliomas and other cancer cell lines accumulation of HIF-1a protein under aerobic conditions requires metabolism of glucose to pyruvate which prevents the aerobic degradation of HIF-1a 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.


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