Abstract 3309: Castration-resistant prostate cancer (CRPC) growth is mediated through gamma-aminobutyric acid a receptor (GABAAR)

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA The GABAergic signaling and growth factor pathways have been implicated in neuroendocrine differentiation and CRPC progression. We hypothesized that the GABAergic signaling and epidermal growth factor receptor (EGFR) pathway worked together to promote prostate cancer (PCa) progression. Using androgen receptor (AR)-negative PC-3 cells and AR-positive LNCaP cells derived from human PCa patients, we demonstrated that both cell lines responded to GABA(10-7M - 10-14M) and isoguvacine [a GABAAR antagonist] (10-7M - 10-11M) treatments over two days with elevated growth in a concentration-dependent manner (n=3 for each). Both GABA and isoguvacine also significantly (p<0.05) stimulated expressions of EGFR ligands (EGF, HB-EGF, and TGF-α) (n=3 for each) in both PCa cell lines as determined by real-time quantitative PCR. Immunoblot analyses indicated significant (p<0.05, n=3) elevation of phosphorylation levels of EGFR (Tyr1068) and downstream signal component Src (Tyr416) after GABA and isoguvacine treatments in both cell types with the same temporal changes as those observed with EGFR ligand expressions. Further involvement of GABAAR and EGFR signaling pathway in GABA and isoguvacine-stimulated PCa cell growth and signal transduction was studied using picrotoxin (a GABAAR antagonist) (10-6M ) and gefitinib (an EGFR inhibitor)( 10-6M). Both picrotoxin and gefitinib significantly (p<0.05, n=3) suppressed the GABA and isoguvacine-stimulated cell growth, as well as EGFR (Tyr1068) and Src (Tyr416) phosphorylation. Immunohistochemical studies of GABAAR α1 and phospho-Src (Tyr416) demonstrated that the presence of these molecules was largely limited to prostate carcinomatous glands, but the levels were extremely low or absent in the normal prostate. In addition, GABAAR α1 and phosphor-Src (Tyr416) were co-localized within the cancerous prostate. Our results demonstrate for the first time, that the GABAergic signaling in CRPC cells is mediated through the EGFR pathway, suggesting that GABA may work as autocrine or paracine to promote PCa progression. The clinical implications of this pathway in CRPC may be of significance by therapeutically targeting the GABAAR pathway. Citation Format: Weijuan Wu. Castration-resistant prostate cancer (CRPC) growth is mediated through gamma-aminobutyric acid a receptor (GABAAR). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3309. doi:10.1158/1538-7445.AM2014-3309