Abstract 5151: Transcriptional regulation of the pyruvate dehydrogenase kinase Pdk2 by tumor suppressors

Abstract

Abstract Conversion of pyruvate into lactate despite the presence of oxygen is a hallmark of the Warburg effect, and distinguishes the metabolism of many tumors from the metabolism of many normal cell types. Pdk2, a pyruvate dehydrogenase kinase, facilitates conversion of pyruvate into lactate by inhibiting the pyruvate dehydrogenase complex, which would otherwise convert pyruvate into acetyl-CoA. Previously, Pdk2 activity was thought to be controlled exclusively in a post-translational fashion, through inhibition or activation by metabolites. But in this study we show that two important tumor suppressor pathways, p53 and retinoblastoma, prevent the Warburg effect, and do so through repression of pdk2 transcription. Importantly, a heterologous promoter that drives physiological expression of Pdk2, but disallows repression by p53 or Rb, prevents these tumor suppressors from blocking the Warburg effect. Another consequence of pdk2 repression is increased production of reactive oxygen species, which stimulates p53-dependent apoptosis. We further show that when unable to downregulate Pdk2 expression, p53 can no longer cause apoptosis. Thus two critical features of tumor suppression, apoptosis and pyruvate metabolism, are mediated by repression of pdk2 transcription. This study proves that proper transcriptional regulation of the pdk2 gene is critical for tumor suppression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5151. doi:1538-7445.AM2012-5151