p53 negatively regulates transcription of the pyruvate dehydrogenase kinase Pdk2.

Cancer Res 2012 Jan 28;72(2):560-7. Epub 2011 Nov 28.

Raymond and Beverly Sackler Foundation, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey, USA.

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.

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http://dx.doi.org/10.1158/0008-5472.CAN-11-1215DOI Listing
January 2012
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