Abstract LB-314: Oncogenic Src drives the Warburg effect and therapy resistance by inactivating pyruvate dehydrogenase through tyrosine phosphorylation

Abstract

Abstract The Warburg effect, which reflects cancer cells’ preference for aerobic glycolysis over glucose oxidation, contributes to tumor growth, progression and therapy resistance. Cancer cells restrain pyruvate flux into mitochondrial oxidative metabolism in large part by inhibiting the pyruvate dehydrogenase (PDH) complex. Src is a prominent oncogenic non-receptor tyrosine kinase that promotes cancer cell proliferation, invasion, metastasis and resistance to conventional and targeted therapies. However, the potential implication of Src in tumor metabolism remained largely unclear. Here we report that active Src enzyme directly tyrosine-phosphorylates the PDH E1α subunit (PDHA1). Conversely, pharmacological Src inhibitors or depletion of Src by shRNA abolish PDHA1 tyrosine phosphorylation in cancer cells, suggesting that Src is the main kinase responsible for PDHA1 tyrosine phosphorylation. This Src-mediated modification inactivates PDH. Consistently, activation of Src attenuates PDH activity and generation of reactive oxygen species (ROS), which are byproducts of mitochondrial respiration. Src inhibitors activate PDH and increase cellular ROS levels. Importantly, expression of a tyrosine non-phosphorable PDHA1 mutant in Src-activated cancer cells restores PDH activity, increases mitochondrial respiration and oxidative stress, decreases experimental metastasis, and sensitizes cancer cells to pro-oxidant treatment. The results suggest that Src contributes to the Warburg metabolic phenotype by inactivating PDH through tyrosine phosphorylation, and this metabolic effect of Src is essential for Src-driven malignancy and therapy resistance. As inhibition of Src sensitizes cancer cells to pro-oxidants, combination therapies consisting of both Src inhibitors and pro-oxidants may improve anticancer efficacy. Citation Format: Jianrong Lu. Oncogenic Src drives the Warburg effect and therapy resistance by inactivating pyruvate dehydrogenase through tyrosine phosphorylation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-314.