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J. Biol. Chem., Vol. 283, Issue 33, 22700-22708, August 15, 2008

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Pyruvate Dehydrogenase Complex Activity Controls Metabolic and Malignant Phenotype in Cancer Cells^*

Thomas McFate, Ahmed Mohyeldin, Huasheng Lu, Jay Thakar, Jeremy Henriques, Nader D. Halim, Hong Wu, Michael J. Schell, Tsz Mon Tsang^¶, Orla Teahan^¶, Shaoyu Zhou^||, Joseph A. Califano, Recipient of a Clinical Innovator Award from the Flight Attendant Medical Research Institute^||**1, Nam Ho Jeoung, Robert A. Harris, and Ajay Verma²

From the Departments of Neurology and Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, the ^¶Department of Biomolecular Medicine, Division of SORA, Imperial College London, South Kensington, London SW7 2AZ, United Kingdom, the ^||Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, the ^**Milton J. Dance Head and Neck Center, Greater Baltimore Medical Center, Baltimore, Maryland 21204, and the Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202

High lactate generation and low glucose oxidation, despite normal oxygen conditions, are commonly seen in cancer cells and tumors. Historically known as the Warburg effect, this altered metabolic phenotype has long been correlated with malignant progression and poor clinical outcome. However, the mechanistic relationship between altered glucose metabolism and malignancy remains poorly understood. Here we show that inhibition of pyruvate dehydrogenase complex (PDC) activity contributes to the Warburg metabolic and malignant phenotype in human head and neck squamous cell carcinoma. PDC inhibition occurs via enhanced expression of pyruvate dehydrogenase kinase-1 (PDK-1), which results in inhibitory phosphorylation of the pyruvate dehydrogenase (PDH) subunit. We also demonstrate that PDC inhibition in cancer cells is associated with normoxic stabilization of the malignancy-promoting transcription factor hypoxia-inducible factor-1 (HIF-1) by glycolytic metabolites. Knockdown of PDK-1 via short hairpin RNA lowers PDH phosphorylation, restores PDC activity, reverts the Warburg metabolic phenotype, decreases normoxic HIF-1 expression, lowers hypoxic cell survival, decreases invasiveness, and inhibits tumor growth. PDK-1 is an HIF-1-regulated gene, and these data suggest that the buildup of glycolytic metabolites, resulting from high PDK-1 expression, may in turn promote HIF-1 activation, thus sustaining a feed-forward loop for malignant progression. In addition to providing anabolic support for cancer cells, altered fuel metabolism thus supports a malignant phenotype. Correction of metabolic abnormalities offers unique opportunities for cancer treatment and may potentially synergize with other cancer therapies.

Received for publication, March 5, 2008 , and in revised form, May 26, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants NS73814 and CA113506 (to A. V.), DK47844 (to R. H.), P50 CA96784 and R01DE015939 from NIDCR (to J. C.) and SPORE grant from NCI. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed: 601 N. Caroline St., 6th Floor, Baltimore, MD 21287-0910. Fax: 410-614-1411; E-mail: jcalifa{at}jhmi.edu. ² To whom correspondence may be addressed: Dept. of Experimental Medicine, Merck & Co., UG4D-34, P. O. Box 1000, North Wales, PA 19454-1099. Fax: 267-305-6384; E-mail: ajay_verma{at}merck.com.

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