Somatostatin, Cortistatin and Their Receptors Exert Antitumor Actions in Androgen-Independent Prostate Cancer Cells: Critical Role of Endogenous Cortistatin

• Published in: International journal of molecular sciences 2022-11, Vol.23 (21), p.13003
• Main Authors: Sáez-Martínez, Prudencio, Porcel-Pastrana, Francisco, Pérez-Gómez, Jesús M., Pedraza-Arévalo, Sergio, Gómez-Gómez, Enrique, Jiménez-Vacas, Juan M., Gahete, Manuel D., Luque, Raúl M.
• Format: Article
• Language: English
• Subjects: AKT protein; Androgens; Antitumor activity; Autocrine signalling; Cancer therapies; Castration; Cell culture; Cell growth; Cyclin-dependent kinases; Down-regulation; Gelatinase B; Gene regulation; Hyperplasia; Kinases; Metastases; Microfluidics; Octreotide; Paracrine signalling; Peptides; Phosphorylation; Prostate cancer; siRNA; Somatostatin
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms232113003

Somatostatin (SST), cortistatin (CORT), and their receptors (SSTR1-5/sst5TMD4-TMD5) comprise a multifactorial hormonal system involved in the regulation of numerous pathophysiological processes. Certain components of this system are dysregulated and play critical roles in the development/progression of different endocrine-related cancers. However, the presence and therapeutic role of this regulatory system in prostate cancer (PCa) remain poorly explored. Accordingly, we performed functional (proliferation/migration/colonies-formation) and mechanistic (Western-blot/qPCR/microfluidic-based qPCR-array) assays in response to SST and CORT treatments and CORT-silencing (using specific siRNA) in different PCa cell models [androgen-dependent (AD): LNCaP; androgen-independent (AI)/castration-resistant PCa (CRPC): 22Rv1 and PC-3], and/or in the normal-like prostate cell-line RWPE-1. Moreover, the expression of SST/CORT system components was analyzed in PCa samples from two different patient cohorts [internal (n = 69); external (Grasso, n = 88)]. SST and CORT treatment inhibited key functional/aggressiveness parameters only in AI-PCa cells. Mechanistically, antitumor capacity of SST/CORT was associated with the modulation of oncogenic signaling pathways (AKT/JNK), and with the significant down-regulation of critical genes involved in proliferation/migration and PCa-aggressiveness (e.g., MKI67/MMP9/EGF). Interestingly, CORT was highly expressed, while SST was not detected, in all prostate cell-lines analyzed. Consistently, endogenous CORT was overexpressed in PCa samples (compared with benign-prostatic-hyperplasia) and correlated with key clinical (i.e., metastasis) and molecular (i.e., SSTR2/SSTR5 expression) parameters. Remarkably, CORT-silencing drastically enhanced proliferation rate and blunted the antitumor activity of SST-analogues (octreotide/pasireotide) in AI-PCa cells. Altogether, we provide evidence that SST/CORT system and SST-analogues could represent a potential therapeutic option for PCa, especially for CRPC, and that endogenous CORT could act as an autocrine/paracrine regulator of PCa progression.