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, Shaw Jenq Tsai

Research output: Contribution to journalArticle

204 Citations (Scopus)

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

Original languageEnglish
Pages (from-to)28106-28114
Number of pages9
JournalJournal of Biological Chemistry
Volume283
Issue number42
DOIs
Publication statusPublished - 2008 Oct 17

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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