Endocrine Abstracts

Somatostatin (SST), Cortistatin (CORT), Neuronostatin (NST) and their receptors [SST/CORT-receptors (sst1–5/sst5TMD4-TMD5) and NST-receptor (GPR107)] comprise a hormonal pleiotropic system involved in the regulation of multiple pathophysiological functions. Certain components of this system are dysregulated in endocrine-related cancers, including prostate cancer (PCa), wherein we have found that alterations in specific components of this regulatory system [i.e. NST-GPR107-circuit/sst1/sst5TMD4 (1–3)] influence their development and progression. However, a comparative, parallel study of the presence and therapeutic role of SST and CORT in PCa has not been reported hitherto. For that reason, we analysed functional parameters (cell proliferation and migration) in response to SST and CORT treatment (10–⁷M) and to siRNA-induced CORT-silencing in different PCa-derived cell lines [androgen-dependent (AD): LNCaP, and androgen-independent (AI): 22Rv1 and PC-3, which are models of hormone-sensitive and Castration-Resistant PCa (CRPCa), respectively], and in the normal prostate cell-line RWPE-1. Moreover, western-blotting and quantitative real-time-PCR were implemented to determine the mechanisms of action associated to SST/CORT treatment and CORT-silencing in PCa cells. SST and CORT treatment significantly inhibited proliferation and migration capacity in AI-PCa cells, but not in AD-PCa or in normal cells. Mechanistically, the antitumor capacity of these peptides was associated to the modulation of important oncogenic signalling-pathways (i.e. AKT/JNK). Interestingly, among all SST-receptors, only sst5 was significantly overexpressed in AI-PCa cells compared to normal-cells, suggesting that the SST/CORT-actions observed in PCa-cells might be mainly exerted through sst5. Remarkably, CORT was highly expressed, while SST transcripts were not detected, in all prostate cell-lines analysed, suggesting that local endogenous CORT could be exerting antitumor actions in PCa-cells through an autocrine/paracrine mechanism. Supporting this idea, CORT-silencing drastically increased the proliferation rate of AI-PCa cells 22Rv1 and PC-3. Finally, CORT expression was correlated with key clinical parameters (i.e. Gleason Score and metastasis) in two in silico cohorts of PCa patients (Grasso/Taylor). Altogether, our results demonstrate that SST/CORT treatment reduced PCa aggressiveness in CRPCa-cells possibly via sst5 and through the alteration of key oncogenic signalling-pathways, suggesting that SST/CORT peptides might be used as therapeutic tool for CRPCa. Moreover, our data revealed that endogenous CORT is highly expressed in PCa cells wherein could exert an auto-regulatory role.

Reference

1. Sáez-Martínez P, et al. 2020. J Clin Med. 9(6):1703.

2. Pedraza-Arévalo S, et al., 2017. Prostate 77(15):1499–1511.

3. Hormaechea-Agulla D, et al., 2017. FASEB J 31(11):4682–4696.

Fundings

MINECO (PID2019–105564RB-I00/FPU18/06009/FPU17–00263), ISCIII (PI16–00264), Junta de Andalucía (BIO-0139) and CIBERobn.