Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells

Thomas McFate, Ahmed Mohyeldin, Huasheng Lu, Jay Thakar, Jeremy Henriques, Nader D. Halim, Hong Wu, Michael J. Schell, Mon Tsang Tsz, Orla Teahan, Shaoyu Zhou, Joseph A. Califano, Ho Jeoung Nam, Robert A. Harris, Ajay Verma

Research output: Contribution to journalArticle

223 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)22700-22708
Number of pages9
JournalJournal of Biological Chemistry
Volume283
Issue number33
DOIs
StatePublished - Aug 15 2008

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells'. Together they form a unique fingerprint.

  • Cite this

    McFate, T., Mohyeldin, A., Lu, H., Thakar, J., Henriques, J., Halim, N. D., Wu, H., Schell, M. J., Tsz, M. T., Teahan, O., Zhou, S., Califano, J. A., Nam, H. J., Harris, R. A., & Verma, A. (2008). Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells. Journal of Biological Chemistry, 283(33), 22700-22708. https://doi.org/10.1074/jbc.M801765200