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The expression of pyruvate dehydrogenase kinase 1and 3 promotes metabolic switch and drug resistance in cancer cells
Author(s) -
Lu ChunWun,
Lin ShihChieh,
Chen KoFan,
Wu ChunWei,
Tsai ShawJenq
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.794.11
Subject(s) - pdk4 , lactate dehydrogenase a , cancer cell , pyruvate dehydrogenase kinase , citric acid cycle , pyruvate dehydrogenase complex , glycolysis , kinase , pkm2 , biology , pyruvate kinase , transfection , lactate dehydrogenase , cell culture , microbiology and biotechnology , cancer research , biochemistry , metabolism , cancer , enzyme , genetics
Metabolic switch from oxidative phosphorylation to aerobic glycolysis is a common phenomenon in cancer cells. However, the underling mechanism is still unclear. Pyruvate dehydrogenase kinase (PDK) inactivates pyruvate dehydrogenase to block tricarboxylic acid (TCA) cycle initiation. Using a bioinformatic approach we identified candidate HRE elements in PDK 1 to 3, but not in PDK4. Therefore, we hypothesized that hypoxia may regulate the expression of PDK to modulate cellular metabolism in cancer cells. Promoter activity assay demonstrated that promoter activities of PDK1 and PDK3 were elevated by hypoxia, and it could be reverse by mutation of HRE. Hypoxia and chemical drugs, such as DFO and DMOG, increased the expressions of PDK1 and PDK3 in several cancer cell lines, such as HeLa and neuroblastoma cancer cell lines. SiRNA assay demonstrated that the hypoxia‐elevated expression of PDK3 was mediated by HIF‐1α, but not by HIF‐2α. Chromatin immunoprecipitation assay provided further evidence that HIF‐1α bound to the PDK3 promoter in vivo . It was known that hypoxia increased lactate production in cancer cells. The hypoxia‐increased lactate production was reversed by knocking down the expression of PDK1 and PDK3. Moreover, lactate production was increased in HeLa cells which transfected with PDK3 under normoxia condition. Furthermore, cells overexpressed PDK3 were more resistance to anticancer drugs. These data demonstrated that increased expression of PDK1 and PDK3 beta;Ψ HIΦ–1α may play important roles in hypoxia‐mediated metabolic switch and drug resistance.