TY - JOUR
T1 - Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells
AU - McFate, Thomas
AU - Mohyeldin, Ahmed
AU - Lu, Huasheng
AU - Thakar, Jay
AU - Henriques, Jeremy
AU - Halim, Nader D.
AU - Wu, Hong
AU - Schell, Michael J.
AU - Tsz, Mon Tsang
AU - Teahan, Orla
AU - Zhou, Shaoyu
AU - Califano, Joseph A.
AU - Nam, Ho Jeoung
AU - Harris, Robert A.
AU - Verma, Ajay
PY - 2008/8/15
Y1 - 2008/8/15
N2 - 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 α (PDHα) subunit. We also demonstrate that PDC inhibition in cancer cells is associated with normoxic stabilization of the malignancy-promoting transcription factor hypoxia-inducible factor-1α (HIF-1α) by glycolytic metabolites. Knockdown of PDK-1 via short hairpin RNA lowers PDHα phosphorylation, restores PDC activity, reverts the Warburg metabolic phenotype, decreases normoxic HIF-1α 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.
AB - 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 α (PDHα) subunit. We also demonstrate that PDC inhibition in cancer cells is associated with normoxic stabilization of the malignancy-promoting transcription factor hypoxia-inducible factor-1α (HIF-1α) by glycolytic metabolites. Knockdown of PDK-1 via short hairpin RNA lowers PDHα phosphorylation, restores PDC activity, reverts the Warburg metabolic phenotype, decreases normoxic HIF-1α 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.
UR - http://www.scopus.com/inward/record.url?scp=53049087909&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=53049087909&partnerID=8YFLogxK
U2 - 10.1074/jbc.M801765200
DO - 10.1074/jbc.M801765200
M3 - Article
C2 - 18541534
AN - SCOPUS:53049087909
SN - 0021-9258
VL - 283
SP - 22700
EP - 22708
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 33
ER -