Document Detail


Induction of pyruvate dehydrogenase kinase-3 by hypoxia-inducible factor-1 promotes metabolic switch and drug resistance.
MedLine Citation:
PMID:  18718909     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Chun-Wun Lu; Shih-Chieh Lin; Ko-Fan Chen; Yen-Yu Lai; Shaw-Jenq Tsai
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-08-21
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  283     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2008 Oct 
Date Detail:
Created Date:  2008-10-13     Completed Date:  2008-11-25     Revised Date:  2013-06-05    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  28106-14     Citation Subset:  IM    
Affiliation:
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, 1 University Road, Tainan 701, Taiwan.
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MeSH Terms
Descriptor/Qualifier:
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*
RNA, Small Interfering / metabolism
Chemical
Reg. No./Substance:
0/Hypoxia-Inducible Factor 1; 0/RNA, Small Interfering; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.2/pyruvate dehydrogenase (acetyl-transferring) kinase
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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