Somatostatin (SST)-system is a pleiotropic hormonal system composed by several ligands/receptors that is involved in the regulation of multiple pathophysiological functions. Specifically, certain components of the SST-system are dysregulated in several endocrine-related cancer types compared to control tissues, wherein these alterations seem to influence their development/progression. However, the presence and functional role of neuronostatin (NST) and its putative G-protein coupled receptor GPR107, two novel members of the SST-system, have not been fully explored in cancer. Consequently, we aimed to investigate the pathophysiological role of NST and GPR107 in prostate cancer (PC), one of the most diagnosed tumors among men worldwide, whose most aggressive phenotype [Castration-Resistant PC (CRPC)] remains lethal nowadays. Functional parameters (cell proliferation and migration) were analysed in response to NST treatment (10−7M) and GPR107-silencing in different PC derived cell-lines [androgen-dependent (AD) LNCaP and androgen-independent (AI) 22Rv1 and PC-3; which are models of hormone-sensitive and CRPC, respectively)], and in normal prostate (NP) cells (RWPE-1 cell-line and primary cell cultures). Moreover, western-blotting, RT-qPCR and microfluidic-based qPCR-array were implemented to determine the mechanisms of actions associated to NST treatment and GPR107-silencing in PC-cells. NST-treatment significantly inhibited proliferation and migration rate in AI-PC cells, but not in AD-PC or in normal-cells (RWPE-1 or primary cell-cultures). Mechanistically, the antitumor capacity of NST was associated with a reduction in GPR107 expression levels, and a significant down-regulation of the expression of key genes involved in proliferation (MKI67/CDK6), migration (MMP9/PRPF40A) and PC-aggressiveness (sst5TMD4/AR-v7/ghrelin/In1-ghrelin/EZH2/MYC) as well as with the modulation of important oncogenic signalling-pathways (ERK/p-ERK; AKT/p-AKT; JNK/p-JNK). Remarkably, these functional antitumor effects exerted by NST on AI-PC cells were blunted after GPR107-silencing, suggesting that the antitumor actions of NST in PC-cells might be mediated via GPR107. Indeed, we found that GPR107 was significantly overexpressed in AI-PC cells compared to RWPE-1 cells, as well as in a cohort of PC samples compared to healthy control adjacent tissues (n=85) and in two in silico-independent samples cohorts (Grasso/Varambally). Finally, GPR107-silencing in AI-PC cells induced a significant decrease in proliferation and migration rate and evoked a similar dysregulation in the expression pattern of key genes previously found in response to NST treatment (i.e. downregulation of MKI67/MMP9/sst5TMD4/AR-v7/ghrelin/In1-ghrelin). Altogether, our results demonstrate that NST treatment reduces PC-aggressiveness in CRPC cells via GPR107 and through the alteration of different key molecular signalling pathways, suggesting that NST/GPR107 system might be considered as a novel therapeutic tool for CRPC.
18 - 21 May 2019
European Society of Endocrinology