Abstract 1257: Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism

Abstract

Abstract Many tumor cells rely on aerobic glycolysis for their continued proliferation and survival, which is in part due to actively inhibited mitochondrial function. Myc and HIF-1 are believed to promote such inhibition by upregulating gene expression of pyruvate dehydrogenase kinase 1 (PDHK1), which phosphorylates and inactivates mitochondrial pyruvate dehydrogenase complex (PDC). However, how oncogenic signals activate PDHK1 to regulate cancer cell metabolism remains unclear. Here we report that oncogenic FGFR1 activates mitochondrial PDHK1 by tyrosine phosphorylation. FGFR1 directly phosphorylates PDHK1 at Y136, Y243 and Y244. Mutational, structural and biochemical studies revealed that phosphorylation at both Y243 and Y244, but not Y136 is required to promote ATP binding to PDHK1, which consequently facilitates PDHK1 binding to PDC scaffold to access substrate PDHA1. In contrast, Y136 phosphorylation may only function to enhance binding between PDHK1 and PDC. We also found that PDHK1 is commonly tyrosine phosphorylated by diverse oncogenic tyrosine kinases in different human cancers. Moreover, we generated cancer cells with stable knockdown of endogenous human PDHK1 and “rescue” expression of phosphorylation-deficient, catalytic hypomorph mouse PDHK1 mutants including Y134F and Y239/240F (mouse PDHK1 numberings correspond to human PDHK1 Y136F and Y243/244F, respectively). These “rescue” cancer cells demonstrated decreased cell proliferation under hypoxia, increased oxidative phosphorylation with decreased lactate production, and reduced tumor growth in xenograft nude mice. Our findings suggest that tyrosine phosphorylation activates PDHK1 to inhibit mitochondrial function, providing a metabolic advantage for tumor growth. This represents a common, short-term molecular mechanism underlying the active inhibition of mitochondrial function in tumor cells, in addition to the chronic changes that are believed to be regulated by Myc and HIF-1. Moreover, inhibition of PDHK1 attenuates tumor growth, suggesting that PDHK1 may serve as a therapeutic target in cancer treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1257. doi:10.1158/1538-7445.AM2011-1257