PMID- 18718909
OWN - NLM
STAT- MEDLINE
DCOM- 20081125
LR  - 20220409
IS  - 0021-9258 (Print)
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Linking)
VI  - 283
IP  - 42
DP  - 2008 Oct 17
TI  - Induction of pyruvate dehydrogenase kinase-3 by hypoxia-inducible factor-1 
      promotes metabolic switch and drug resistance.
PG  - 28106-14
LID - 10.1074/jbc.M803508200 [doi]
AB  - 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.
FAU - Lu, Chun-Wun
AU  - Lu CW
AD  - Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung 
      University, 1 University Road, Tainan 701, Taiwan.
FAU - Lin, Shih-Chieh
AU  - Lin SC
FAU - Chen, Ko-Fan
AU  - Chen KF
FAU - Lai, Yen-Yu
AU  - Lai YY
FAU - Tsai, Shaw-Jenq
AU  - Tsai SJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20080821
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (PDK3 protein, human)
RN  - 0 (Pyruvate Dehydrogenase Acetyl-Transferring Kinase)
RN  - 0 (RNA, Small Interfering)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
SB  - IM
MH  - Cell Differentiation
MH  - Cell Hypoxia
MH  - Cell Line, Tumor
MH  - Cell Survival
MH  - Chromatin Immunoprecipitation
MH  - *Drug Resistance
MH  - *Drug Resistance, Neoplasm
MH  - *Gene Expression Regulation
MH  - *Gene Expression Regulation, Neoplastic
MH  - HeLa Cells
MH  - Humans
MH  - Hypoxia-Inducible Factor 1/*genetics
MH  - Models, Biological
MH  - Protein Serine-Threonine Kinases/*biosynthesis
MH  - Pyruvate Dehydrogenase Acetyl-Transferring Kinase
MH  - RNA, Small Interfering/metabolism
PMC - PMC2661383
EDAT- 2008/08/23 09:00
MHDA- 2008/12/17 09:00
PMCR- 2009/10/17
CRDT- 2008/08/23 09:00
PHST- 2008/08/23 09:00 [pubmed]
PHST- 2008/12/17 09:00 [medline]
PHST- 2008/08/23 09:00 [entrez]
PHST- 2009/10/17 00:00 [pmc-release]
AID - S0021-9258(20)64207-7 [pii]
AID - 28106 [pii]
AID - 10.1074/jbc.M803508200 [doi]
PST - ppublish
SO  - J Biol Chem. 2008 Oct 17;283(42):28106-14. doi: 10.1074/jbc.M803508200. Epub 2008 
      Aug 21.