Abstract 997: Oncogenic tyrosine kinases are localized to mitochondria and regulate cancer metabolism by phosphorylating key components of pyruvate dehydrogenase kinase complex

Abstract

Abstract The Warburg effect describes the observation that cancer cells take up more glucose than normal tissue and favor aerobic glycolysis. Many tumor cells rely on aerobic glycolysis instead of mitochondrial oxidative phosphorylation for their continued proliferation and survival. This may be, in part, due to attenuated mitochondrial function, which is suggested to be achieved through inhibition of pyruvate dehydrogenase complex (PDC) in cancer cells. Pyruvate dehydrogenase (PDH) is the first and most important enzyme component of PDC, which catalyzes the conversion of pyruvate to acetyl-CoA that subsequently enters into the Krebs cycle to produce ATP and electron donors including NADH. PDH activity is negatively regulated by phosphorylation at several serine sites. Phosphorylation of PDH by PDH kinase (PDHK) results in the inactivation of PDC, while dephosphorylation by pyruvate dehydrogenase phosphatase (PDP) restores PDC activity. Thus, PDHK and PDP coordinate to regulate the phosphorylation and consequently activation status of PDH. In cancer cells, c-Myc and HIF-1alpha are believed to promote inhibition of PDC by, in part, upregulating gene expression of PDHK. However, how oncogenic signals regulate PDH, and/or coordinate PDHK and PDP activity to inhibit PDH and ultimately attenuate PDC activity in cancer metabolism still remains unclear. We recently reported that, surprisingly, functional PDC can form in mitochondria outside of matrix in some cancer cells. Moreover, several oncogenic tyrosine kinases including FGFR1, FGFR1 fusion tyrosine kinase, and FLT3-ITD mutant, as well as BCR-ABL and JAK2 V617F mutants, are localized to different mitochondrial compartments including outer membrane and matrix, respectively, in cancer cells, where they phosphorylate PDHK1, PDP1 and PDHA. Our studies demonstrate that tyrosine phosphorylation enhances PDHK1 kinase activity by promoting ATP and PDC binding, which promotes cancer cell metabolism, proliferation and tumor growth. In consonance with these findings, we found that tyrosine phosphorylation attenuates PDP1 phosphatase activity but inhibits PDHA enzyme activity. These data suggest that mitochondrial oncogenic tyrosine kinases regulate PDC activity by inhibiting PDHA1 enzyme activity directly through tyrosine phosphorylation and indirectly by enhancing and attenuating PDHK1 and PDP1 activity, respectively. These findings represent an acute mechanism underlying the Warburg effect, in addition to the long-term regulation that is believed to be regulated by c-Myc and HIF-1alpha. 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 997. doi:1538-7445.AM2012-997