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Originally published In Press as doi:10.1074/jbc.M202487200 on April 9, 2002

J. Biol. Chem., Vol. 277, Issue 26, 23111-23115, June 28, 2002
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Hypoxia-inducible Factor 1 Activation by Aerobic Glycolysis Implicates the Warburg Effect in Carcinogenesis*

Huasheng Lu, Robert A. Forbes, and Ajay VermaDagger

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

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.

* This work was supported in part by National Institutes of Health Grant NS-37814 and Department of Defense Grants MDA905-92-Z-0003 and MDA905-00-1-0034 (to A. V.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Dept. of Neurology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814. Tel.: 301-295-3840; Fax: 301-295-3825; E-mail: averma@usuhs.mil.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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