Unsuspected Protumorigenic Signaling Role for the Oncometabolite GABA in Advanced Prostate Cancer.

Elucidating the events that underpin the transition from androgen-dependent to castrate-resistant prostate cancer (CRPC) remains a clinical challenge. In this issue of Cancer Research, Gao and colleagues identify that the γ-aminobutyric acid (GABA) shunt is upregulated with the onset of CRPC, via phosphorylation and activation of glutamate decarboxylase (GAD) 65. Overproduction of GABA, an oncometabolite, can directly regulate nuclear androgen receptor signaling to drive tumorigenesis, thereby providing a link between aberrant metabolism and protumorigenic signaling in advanced prostate cancer. The findings from this study support exploring the GABA shunt, GAD65 in particular, as a molecular target in the treatment of CRPC.See related article by Gao et al., p. 4638. ©2019 American Association for Cancer Research.