Unleashing the Diagnostic, Prognostic and Therapeutic Potential of the Neuronostatin/GPR107 System in Prostate Cancer.

Prudencio Sáez-Martínez,Vicente Herrero-Aguayo,Juan M Jiménez-Vacas,Antonio J León-González,Justo P Castaño,Rafael Sánchez-Sánchez,Manuel D Gahete,Antonio J Montero Hidalgo,María J Requena-Tapia,Raúl M Luque,Enrique Gómez-Gómez

doi:10.3390/jcm9061703

Abstract

Certain components of the somatostatin-system play relevant roles in Prostate Cancer (PCa), whose most aggressive phenotype (Castration-Resistant-PCa (CRPC)) remains lethal nowadays. However, neuronostatin and the G protein-coupled receptor 107 (GPR107), two novel members of the somatostatin-system, have not been explored yet in PCa. Consequently, we investigated the pathophysiological role of NST/GPR107-system in PCa. GPR107 expression was analyzed in well-characterized PCa patient′s cohorts, and functional/mechanistic assays were performed in response to GPR107-silencing and NST-treatment in PCa cells (androgen-dependent (AD: LNCaP) and androgen-independent (AI: 22Rv1/PC-3), which are cell models of hormone-sensitive and CRPC, respectively), and normal prostate cells (RWPE-1 cell-line). GPR107 was overexpressed in PCa and associated with key clinical parameters (e.g., advance stage of PCa, presence of vascular invasion and metastasis). Furthermore, GPR107-silencing inhibited proliferation/migration rates in AI-PCa-cells and altered key genes and oncogenic signaling-pathways involved in PCa aggressiveness (i.e., KI67/CDKN2D/MMP9/PRPF40A, SST5TMD4/AR-v7/In1-ghrelin/EZH2 splicing-variants and AKT-signaling). Interestingly, NST treatment inhibited proliferation/migration only in AI-PCa cells and evoked an identical molecular response than GPR107-silencing. Finally, NST decreased GPR107 expression exclusively in AI-PCa-cells, suggesting that part of the specific antitumor effects of NST could be mediated through a GPR107-downregulation. Altogether, NST/GPR107-system could represent a valuable diagnostic and prognostic tool and a promising novel therapeutic target for PCa and CRPC.

Highlights

Prostate cancer (PCa) is one of the most diagnosed tumor pathologies among men worldwide and represents one of the leading causes of cancer-related death among the male population in developed countries [1]
Analysis of G protein-coupled receptor 107 (GPR107) messenger RNA (mRNA) expression in FFPE-prostate pieces from patients diagnosed with localized PCa (n = 84; Gleason score 6–8; Table 1) revealed that GPR107 expression was significantly higher in tumor vs. non-tumor adjacent regions (N-TAR; Figure 1a)
GPR107 IHC analysis was performed on 16 FFPE pieces (Figure 1b), which revealed that GPR107 staining was negligible in benign prostate gland epithelium (N-TAR; Figure 1b), while it was always more, and highly, intense in the cancerous prostate glands (N-TAR vs. PCa/tumor-tissue; Figure 1b)

Summary

Introduction

Prostate cancer (PCa) is one of the most diagnosed tumor pathologies among men worldwide and represents one of the leading causes of cancer-related death among the male population in developed countries [1]. The development of these drugs has significantly improved the overall survival, some PCa patients acquire resistance to these compounds and develop the most aggressive phenotype, named Castration-Resistant PCa (CRPC), which remains lethal nowadays [3,4,5]. For this reason, new therapeutic targets in order to tackle PCa and CRPC are urgently required. The mechanistic reasons of those clinical failures are still unknown, but it has been suggested that one of the causes might be the overexpression of the spliced variant SST5TMD4 in PCa cells, which hampers the normal response to somatostatin-analogs in PCa-cells [11]

Results

Discussion

Conclusion