TMET-06. METABOLIC FATE OF OXALOACETATE IN GLIOBLASTOMA

Abstract Oxaloacetate (OAA) inhibits the Warburg effect by reducing glucose-derived lactate levels in human cancer cell lines. In dose ranging IC50 experiments with hepatocellular carcinoma (HCC) lines, OAA inhibited growth concentration range 1.7 - 2.4 mM. Previously, we showed that presence of OAA, [U-13C]glucose derived was reduced 48.8% GBM cells. also increased survival mouse models GBM. Here, are showing an evidence for direct utilization Glioblastoma (GBM) cells, using uniformly 13C-labeled oxaloacetate ([U-13C]OAA) as a metabolic tracer. Patient-derived cells were grown DMEM medium containing 11.0 mM glucose and 2.0 glutamine. When reached confluency, treated 4.0 [U-13C]OAA above medium. GC-MS based 13C isotopomer analysis entered get metabolized to generate distinct isotopomers aspartate, citrate, glutamate, malate fumarate. Upon entering TCA cycle, generated M+4 aspartate (3.0%) citrate (3.2%), M+3 glutamate (4.1%). During first turn it produced M+2 (13.9%), (10.5%), fumarate (8.8%), after multiple turns, led production following isotopomers: (21.5%), (17.2%), M+1 (5.6%) (2.2%). addition, [U-13C]pyruvate (17.0%) through PEPCK/PK/ or malic enzyme which further similar amount [U-13C]lactate [U-13C]alanine (12%). These data demonstrate utilize perturb cycle glycolytic pathways, support our previous observation OAA-derived pyruvate lead increase total pool associated decrease flux including lactate. may metabolically reduce tumor difficult treat cancers.