Abstract 4379: Prostate cancer cells utilize the GABA shunt to enhance oxidative metabolism

Abstract

Although an upregulation of aerobic glycolysis (the Warburg effect) is a canonical hallmark of cancer, it is now recognized that most cancerous cells continue to rely on the TCA cycle as a source of both biosynthetic precursors (DeBarardinis & Chandel, 2016) and the majority of ATP production (Zu & Guppy, 2004). Drug-resistant cancers have been associated with metabolic reprogramming (Rahman & Hasan, 2015) involving an upregulation in oxidative phosphorylation (Wolf, 2014). Two advanced, treatment-resistant variants of prostate cancer are castration-resistant adenocarcinoma (CRPC-adeno) and neuroendocrine prostate cancer (NEPC). Emerging evidence suggests that the γ-aminobutyric acid (GABA) shunt—an evolutionarily conserved pathway for energy production, biosynthetic precursors, and ROS management—may be used by both CRPC-adeno and NEPC. The GABA shunt is a bypass for two steps of the TCA cycle, wherein GABA is synthesized from glutamate by a GAD1-encoded decarboxylase, transaminated into succinic semialdehyde, and metabolized into the TCA cycle intermediate succinate. Analysis of publicly available transcript datasets (via cBioPortal) indicates that GAD1 mRNA expression increases with increasing Gleason score (p Citation Format: Erika L. Knott, Sumitra Miriyala, Manikandan Panchatcharam, Nancy Leidenheimer. Prostate cancer cells utilize the GABA shunt to enhance oxidative metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4379.