Abstract B05: PI3K/mTOR pathway-dependent regulation of oxygen metabolism via pyruvate dehydrogenase (PDH)-E1alpha phosphorylation

Abstract

Abstract The PI3K/mTOR pathway plays a central role in coupling metabolic processes to the cellular proliferative state. In the current study we show that pharmacological inhibition of this pathway leads to a decrease in hypoxia within SQ20B human head and neck cancer xenografts. The mechanism underlying the effect appears in part to be due to reduced tumor cell oxygen consumption induced by the drug. Pharmacologic inhibitors of the PI3K/mTOR pathway or genetic inhibition of Akt/PI3K decreased the oxygen consumption rate (OCR) in transformed cell lines in vitro by 30-40%. Pharmacologic inhibition of this pathway increased phosphorylation of the E1alpha subunit of the pyruvate dehydrogenase (PDH) complex on Ser293, an inhibitory modification of this critical gatekeeper of mitochondrial respiration. Expressing wild type PTEN in a doxycycline-inducible manner in a glioblastoma cell line with mutant PTEN led to an increase in PDH-E1alpha phosphorylation and a decrease in OCR. The decrease in OCR with PI3K/Akt/mTOR inhibition was recapitulated by knocking down PDH-E1alpha expression using siRNA. Pre-treatment with dichloroacetate (DCA), a known inhibitor of the pyruvate dehydrogenase kinases (PDKs) that phosphorylate PDH-E1alpha prevented the upregulation in PDH-E1alpha phosphorylation, induced by inhibition of the pathway and also blunted the decrease in OCR. Our findings highlight an association between the PI3K/mTOR pathway and tumor cell oxygen consumption and reveal a novel link between this pathway and PDH phosphorylation. These results have important implications for understanding the effects PI3K pathway activation in tumor metabolism and also in the use of inhibitors of this pathway in cancer therapy Citation Format: George Cerniglia, Souvik Dey, Shannon M. Gallagher-Colombo, Natalie Daurio, Stephen Tuttle, Theresa M. Busch, Alexander Lin, Tatiana V. Esipova, Sergei Vinogradov, Constantinos Koumenis, Amit Maity. PI3K/mTOR pathway-dependent regulation of oxygen metabolism via pyruvate dehydrogenase (PDH)-E1alpha phosphorylation. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B05.