DDRE-18. THE MITOCHONDRIAL PYRUVATE CARRIER—A METABOLIC TARGET OF MALIGNANT GLIOMA

Abstract

Metabolic reprogramming has been recognized as crucial to the survival and proliferation of cancer cells through the reduction of glucose oxidation (the Warburg effect) and diversion of pyruvate and glycolytic metabolites to fuel anabolic processes. The mitochondrial pyruvate carrier (MPC) protein complex, consisting of MPC1 and MPC2, has been identified as essential for pyruvate transport into mitochondria. In most human cancers, MPC1 is frequently deleted or downregulated and, therefore, the MPC activity is low. Restoration of MPC levels increases pyruvate oxidation and markedly inhibits tumor growth. Despite being tumor suppressive in general, the role of MPC in malignant glioma seems complex. We reported previously that unlike MPC1 in IDH-mutant glioma, MPC2 expression correlated with worsened survival. Interestingly, MPC2 homo-oligomers have been identified recently as an efficient autonomous pyruvate transporter, which can be inhibited by an insulin sensitizer rosiglitazone but not by the MPC heterotypic oligomer inhibitor UK-5099. In this study, we report that glioma cells show low MPC1 expression but much higher MPC2 expression. Analysis of glioma patient data revealed that the mean MPC2 expression increased in a grade-dependent fashion whereas the mean MPC1 expression remained essentially low, thereby resulting in an increased MPC2/MPC1 ratio in association with glioma progression. Importantly, we show that malignant glioma cells are extremely sensitive to the mitochondrion-specific, PPARγ-sparing insulin sensitizer mitoglitazone but not UK-5099 whereas MPC-proficient glial cells are highly responsive to the latter, indicating MPC2 as an alternative pyruvate transporter in glioma. Furthermore, the addition of glutamate fully rescues the growth arrest of Mpc1-/- murine glial cells, suggesting the involvement of cerebral cortex-specific microenvironment in glioma growth. We are employing newly developed RCAS/tva Mpc1fl/fl mouse models to test therapeutic targeting of Mpc2 in spontaneously developed glioma.