Tumor and Stem Cell Biology p53 Negatively Regulates Transcription of the Pyruvate Dehydrogenase Kinase Pdk2

In cancer cells, the aberrant conversion of pyruvate into lactate instead of acetyl-CoA in the presence of oxygen is known as theWarburg effect. The consequences andmechanisms of thismetabolic 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 formof 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, wildtype 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 newmechanism by which p53 suppresses tumorigenesis acting at the level of cancer cell metabolism. Cancer Res; 72(2); 560–7. 2011 AACR.