Estrogens Modulate Somatostatin Receptors Expression and Synergize With the Somatostatin Analog Pasireotide in Prostate Cells

Abstract

Prostate cancer (PC) is one of the most frequently diagnosed cancers and a leading cause of cancer-related deaths in Western society. Current PC therapies prevalently target the functions of androgen receptor (AR) and may only be effective within short time periods, beyond which the majority of PC patients progress to castration-resistant PC (CRPC) and metastatic disease. The role of estradiol/estradiol receptor (ER) axis in prostate transformation and PC progression is well established. Further, considerable efforts have been made to investigate the mechanism by which somatostatin (SST) and somatostatin receptors (SSTRs) influence PC growth and progression. A number of therapeutic strategies, such as the combination of SST analogs with other drugs, show, indeed, strong promise. However, the effect of the combined treatment of SST analogs and estradiol on proliferation, epithelial mesenchyme transition (EMT) and migration of normal- and cancer-derived prostate cells has not been investigated so far. We now report that estradiol plays anti-proliferative and pro-apoptotic effect in non-transformed EPN prostate cells, which express both ERα and ERβ. A weak apoptotic effect is observed in transformed CPEC cells that only express low levels of ERβ. Estradiol increases, mainly through ERα activation, the expression of SSTRs in EPN, but not CPEC cells. As such, the hormone enhances the anti-proliferative effect of the SST analog, pasireotide in EPN, but not CPEC cells. Estradiol does not induce EMT and the motility of EPN cells, while it promotes EMT and migration of CPEC cells. Addition of pasireotide does not significantly modify these responses. Altogether, our results suggest that pasireotide may be used, alone or in combination with other drugs, to limit the growth of prostate proliferative diseases, provided that both ER isoforms (α and β) are present. Further investigations are needed to better define the cross talk between estrogens and SSTRs as well as its role in PC.

Estrogen Receptors Promote Migration, Invasion and Colony Formation of the Androgen-Independent Prostate Cancer Cells PC-3 Through β-Catenin Pathway

“…On the other hand, ERα-selective agonist PPT did not modify cell migration. Consistent with these results, study has shown that the activation of ERβ by DPN also promotes survival and migration of CPEC cell line, established from prostate cancer patients (19). Furthermore, the expression of ERβ5 (ERβ splice variant) in PC-3 cells increased the cell migration, and the expression of ERβ2 and ERβ5 increased the invasion, but did not change the proliferation of the cells (39).…”

“…The expression of estrogen receptors ERα and ERβ changes in different stages of the prostate cancer and conflicting findings on the roles of these receptors in the prostate cancer continue to emerge [reviewed by (11)(12)(13)(14)(15)]. However, studies have shown that ERβ may be potentially oncogenic in prostate cancer (16)(17)(18)(19).…”

The Crosstalk between Prostate Cancer and Microbiota Inflammation: Nutraceutical Products Are Useful to Balance This Interplay?

“…Parallel studies in TRAMP-FVB mice showed that a low-dose genistein diet (250 mg/kg) promoted PCa growth and metastasis compared to control and a high-dose genistein diet (1000 mg/kg), showing a biphasic effect of isoflavones on PCa [142]. Paller et al found that an increase in quercetin intake, another well-known isoflavone contained in capers, leads to a reduced risk of PCa, in African-Americans with vitamin D deficiency, while Sun et al showed that its use, associated with metformin, inhibits the growth, migration, and invasion on PC3 and LNCaP cells by inhibiting the VEGF/AKT/PI3K signaling pathway [143,144]. Similarly, fisetin has been suggested to act as a dual inhibitor on PI3K/AKT and mTOR metabolic pathways in PCa cell lines.…”

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

“…In this sense, certain components of the somatostatin system, especially somatostatin-receptors (SST 1-5 , encoded by the somatostatin receptor 1-5 genes (SSTR1-5)), are expressed in both normal and tumor prostate tissues, where they may play a relevant role in the development and progression of this disease [6][7][8][9]. Specifically, some components of this system (e.g., SST 1 and SST 2 ) can contribute to reduce different tumor parameters, including cell proliferation and migration, whereas other components [i.e., the truncated splicing variant of SST 5 with four transmembrane domains (SST 5 TMD4 variant)] promote aggressiveness features of PCa [10][11][12].…”