p53 negatively regulates transcription of the pyruvate dehydrogenase kinase Pdk2

Cancer Res. 2012 Jan 15;72(2):560-7. doi: 10.1158/0008-5472.CAN-11-1215. Epub 2011 Nov 28.

Abstract

In cancer cells, the aberrant conversion of pyruvate into lactate instead of acetyl-CoA in the presence of oxygen is known as the Warburg effect. The consequences and mechanisms of this metabolic peculiarity are incompletely understood. Here we report that p53 status is a key determinant of the Warburg effect. Wild-type p53 expression decreased levels of pyruvate dehydrogenase kinase-2 (Pdk2) and the product of its activity, the inactive form of the pyruvate dehydrogenase complex (P-Pdc), both of which are key regulators of pyruvate metabolism. Decreased levels of Pdk2 and P-Pdc in turn promoted conversion of pyruvate into acetyl-CoA instead of lactate. Thus, wild-type p53 limited lactate production in cancer cells unless Pdk2 could be elevated. Together, our results established that wild-type p53 prevents manifestation of the Warburg effect by controlling Pdk2. These findings elucidate a new mechanism by which p53 suppresses tumorigenesis acting at the level of cancer cell metabolism.

MeSH terms

  • Animals
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Genes, p53
  • HCT116 Cells
  • Humans
  • Lactates / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Protein Binding
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Transcription, Genetic
  • Transfection
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Lactates
  • PDK2 protein, human
  • Pdk2 protein, mouse
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Protein-Serine-Threonine Kinases