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

Abstract

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 GABAB 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 GABAB 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.

Competing Endogenous RNA and Coexpression Network Analysis for Identification of Potential Biomarkers and Therapeutics in association with Metastasis Risk and Progression of Prostate Cancer

“…The relationship between GABRG1 and cancer has not yet been reported. Presently, using enrichment analysis, we confirmed that the GABAergic system contributes to PCa progression [39]. It has also been reported that GABA is highly expressed in prostate tissue of patients with cancer or benign prostatic hypertrophy and the high expression has been observed in prostate tissue of cancer patients with LNM [66].…”

“…Neuroactive ligand-receptor interaction, especially the GABAergic system, has significant effects on the progression of PCa. The GABAergic system is enriched in neuroendocrine cell- (NE-) like cells [38] and contributes to PCa progression due to the secretion of neuropeptides [39].…”

Testosterone Promotes Glioblastoma Cell Proliferation, Migration, and Invasion Through Androgen Receptor Activation

“…The participation of androgens in several physiological and pathological processes in the CNS has been widely described (5). It is also known that they are involved in prostate, colon and lung cancer growth (11, 19–21). Epidemiological data report that GBM occur in a greater proportion in men than in women (3:2), which suggests androgens participation in the development of these tumors.…”

Identification of aberrantly methylated differentially expressed genes in prostate carcinoma using integrated bioinformatics

“…Studies have shown that ubiquitin-mediated proteolysis, endocytosis, and focal adhesion pathways can impact PCa development and progression in different ways [45–47]. In addition, in the GABAergic synapse pathway, GABA induces GRP secretion via GABBR1 in neuroendocrine-like cells, which is involved in PCa progression [48]. The cell cycle is a vital cellular process involving DNA replication and translation, and it tends to be deregulated in cancer [49].…”