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PMID: 18718909 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Induction of pyruvate dehydrogenase kinase-3 by hypoxia-inducible factor-1 promotes metabolic switch and drug resistance.

The Journal of biological chemistry ·Vol. 283 ·No. 42 ·2008-10-17 ·Pages 28106-14

Lu CW, Lin SC, Chen KF, Lai YY, Tsai SJ

Abstract

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-1alpha in cancer cells may play critical roles in metabolic switch during cancer progression and chemoresistance in cancer therapy.

MeSH Terms
Cell Differentiation Cell Hypoxia Cell Line, Tumor Cell Survival Chromatin Immunoprecipitation Drug Resistance Drug Resistance, Neoplasm Gene Expression Regulation Gene Expression Regulation, Neoplastic HeLa Cells Humans Hypoxia-Inducible Factor 1/genetics Models, Biological Protein Serine-Threonine Kinases/biosynthesis Pyruvate Dehydrogenase Acetyl-Transferring Kinase RNA, Small Interfering/metabolism
Chemicals
Hypoxia-Inducible Factor 1 PDK3 protein, human Pyruvate Dehydrogenase Acetyl-Transferring Kinase RNA, Small Interfering Protein Serine-Threonine Kinases
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Lu Chun-Wun
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, 1 University Road, Tainan 701, Taiwan.
Lin Shih-Chieh
Chen Ko-Fan
Lai Yen-Yu
Tsai Shaw-Jenq
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Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
0021-9258
DOI
10.1074/jbc.M803508200
Published
2008-10-17
Epub
2008-00-21
Pages
28106-14
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC2661383
Subset
IM
External Links
PubMed source DOI: 10.1074/jbc.M803508200 PMC Full Text View journal details
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