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J. Biol. Chem., Vol. 283, Issue 42, 28106-28114, October 17, 2008

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Induction of Pyruvate Dehydrogenase Kinase-3 by Hypoxia-inducible Factor-1 Promotes Metabolic Switch and Drug Resistance^*

Chun-Wun Lu, Shih-Chieh Lin, Ko-Fan Chen, Yen-Yu Lai, and Shaw-Jenq Tsai¹

From the Institute of Basic Medical Sciences and Department of Physiology, College of Medicine, National Cheng Kung University, 1 University Road, Tainan 701, Taiwan

The switch of cellular metabolism from mitochondrial respiration to glycolysis is the hallmark of cancer cells and associated with tumor malignancy. However, the mechanism of this metabolic switch remains largely unknown. Herein, we reported that hypoxia-inducible factor-1 (HIF-1) induced pyruvate dehydrogenase kinase-3 (PDK3) expression leading to inhibition of mitochondrial respiration. Promoter activity assay, small interference RNA knockdown assay, and chromatin immunoprecipitation assay demonstrated that hypoxia-induced PDK3 gene activity was regulated by HIF-1 at the transcriptional level. Forced expression of PDK3 in cancer cells resulted in increased lactic acid accumulation and drugs resistance, whereas knocking down PDK3 inhibited hypoxia-induced cytoplasmic glycolysis and cell survival. These data demonstrated that increased PDK3 expression due to elevated HIF-1 in cancer cells may play critical roles in metabolic switch during cancer progression and chemoresistance in cancer therapy.

Received for publication, May 8, 2008 , and in revised form, August 21, 2008.

^* This work was supported by the National Research Program of Genome Medicine (Grant NSC94-3112-B-006-010) and the Landmark Project (Grant A-0123) of National Cheng Kung University, Taiwan. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ To whom correspondence should be addressed. Tel.: 886-6-235-3535 (ext. 5426); Fax: 886-6-236-2780; E-mail: seantsai{at}mail.ncku.edu.tw.

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