Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells.
High lactate generation and low glucose oxidation, despite normal oxygen conditions, are commonly seen in cancer cells and tumors. Historically known as the Warburg effect, this altered metabolic phenotype has long been correlated with malignant progression and poor clinical outcome. However, the mechanistic relationship between altered glucose metabolism and malignancy remains poorly understood. Here we show that inhibition of pyruvate dehydrogenase complex (PDC) activity contributes to the Warburg metabolic and malignant phenotype in human head and neck squamous cell carcinoma. PDC inhibition occurs via enhanced expression of pyruvate dehydrogenase kinase-1 (PDK-1), which results in inhibitory phosphorylation of the pyruvate dehydrogenase alpha (PDHalpha) subunit. We also demonstrate that PDC inhibition in cancer cells is associated with normoxic stabilization of the malignancy-promoting transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha) by glycolytic metabolites. Knockdown of PDK-1 via short hairpin RNA lowers PDHalpha phosphorylation, restores PDC activity, reverts the Warburg metabolic phenotype, decreases normoxic HIF-1alpha expression, lowers hypoxic cell survival, decreases invasiveness, and inhibits tumor growth. PDK-1 is an HIF-1-regulated gene, and these data suggest that the buildup of glycolytic metabolites, resulting from high PDK-1 expression, may in turn promote HIF-1 activation, thus sustaining a feed-forward loop for malignant progression. In addition to providing anabolic support for cancer cells, altered fuel metabolism thus supports a malignant phenotype. Correction of metabolic abnormalities offers unique opportunities for cancer treatment and may potentially synergize with other cancer therapies.
Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, USA.
Thomas
T
McFate
Ahmed
A
Mohyeldin
Huasheng
H
Lu
Jay
J
Thakar
Jeremy
J
Henriques
Nader D
ND
Halim
Hong
H
Wu
Michael J
MJ
Schell
Tsz Mon
TM
Tsang
Orla
O
Teahan
Shaoyu
S
Zhou
Joseph A
JA
Califano
Nam Ho
NH
Jeoung
Robert A
RA
Harris
Ajay
A
Verma
D002455:Cell Division; D002467:Cell Nucleus / Q000201:enzymology; D002470:Cell Survival; D003600:Cytosol / Q000201:enzymology; D006019:Glycolysis; D006258:Head and Neck Neoplasms / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007700:Kinetics; D009361:Neoplasm Invasiveness; D011768:Pyruvate Dehydrogenase Complex / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011768:Pyruvate Dehydrogenase Complex