Abstract 1000: Oncogenic Kras inhibits mitochondrial metabolism by regulating the pyruvate dehydrogenase complex under conditions of nutrient stress

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Kras is one of the most frequently mutated oncogenes in human cancer. Previous studies have suggested a role for oncogenic Kras in regulating glucose metabolism, although the exact mechanism is unclear. By analyzing the transcriptional consequences of Kras mutation under conditions of nutrient stress, a direct role for oncogenic Kras in regulating oxidative phosphorylation was observed. Signaling downstream of Kras via the MEK/ERK pathway inhibits expression of PDP1, a mitochondrial phosphatase that regulates the pyruvate dehydrogenase complex (PDC). PDC is a key enzyme in the conversion of pyruvate into acetyl-CoA. Decreased expression of PDP1 induced by oncogenic Kras leads to increased phosphorylation and thereby inactivation of PDC. Therefore, oncogenic Kras represses mitochondrial function and oxygen consumption by maintaining PDC in an inactive state. This effect is not apparent under the high-glucose conditions in which cells are typically cultured. However, at glucose concentrations more closely reflective of what cells experience in vivo, the effect of oncogenic Kras signaling on PDP1 expression becomes readily apparent. This study demonstrates a novel role for oncogenic Kras in the regulation of mitochondrial metabolism. Further studies underway may clarify a role for this pathway as a target for therapeutic intervention in Kras-mutant tumors. 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 1000. doi:1538-7445.AM2012-1000