Induction of Pyruvate Dehydrogenase Kinase-3 by Hypoxia-inducible Factor-1 Promotes Metabolic Switch and Drug ResistanceS
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 d...
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Published in | The Journal of biological chemistry Vol. 283; no. 42; pp. 28106 - 28114 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
American Society for Biochemistry and Molecular Biology
17.10.2008
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Subjects | |
Online Access | Get full text |
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Summary: | 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-1α
in cancer cells may play critical roles in metabolic switch during cancer
progression and chemoresistance in cancer therapy. |
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Bibliography: | To whom correspondence should be addressed. Tel.: 886-6-235-3535 (ext. 5426); Fax: 886-6-236-2780; E-mail: seantsai@mail.ncku.edu.tw. 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. |
ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M803508200 |