GABA promotes gastrin-releasing peptide secretion in NE/NE-like cells: Contribution to prostate cancer progression

In prostate cancer (PCa), neuroendocrine cells (NE) have been associated with the progression of the disease due to the secretion of neuropeptides that are capable of diffusing and influence surrounding cells. The GABAergic system is enriched in NE-like cells, and contributes to PCa progression. Additionally, γ-aminobutyric acid (GABA) stimulates the secretion of gastrin-releasing peptide (GRP) in peripheral organs. For the first time, in this study we show the role of GABA and GABA_B receptor 1 (GABBR1) expression in GRP secretion in NE-like prostate cancer cells. We demonstrated an increase in GRP levels in NE-like cell medium treated with GABA_B receptor agonist. Moreover, the blocking of this receptor inhibited GABA-induced GRP secretion. The invasive potential of PC3 cells was enhanced by either GRP or conditioned medium of NE-like cells treated with GABA. Additionally, we confirmed a positive correlation between GABA and GRP levels in the serum of PCa patients with NE markers. Finally, using public available data sets, we found a negative correlation between GABBR1 and androgen receptor (AR) expression, as well as a strong positive correlation between GABBR1 and enolase 2. These results suggest that GABA via GABBR1 induces GRP secretion in NE like cells involved in PCa progression.