Mineralocorticoid receptor signaling affects therapeutic effect of enzalutamide

Abstract

MR plays a critical role in resistance to AR-targeting therapies, which may be overcome by activation of MR signaling.

The Role of Mineralocorticoid Receptor Signaling in Genitourinary Cancers

“…retinoid X receptor (RXR ) [34], AR) have been separately indicated. Meanwhile, MR protein expression was confirmed in all 4 human prostate cancer cell lines examined [35]. MR gene expression was shown to be comparable between normal prostate and prostate cancer tissue specimens [35] and was detected 1 of 2 lines included in the cell panel for the expression profiling [18].…”

“…MR signals have also been suggested to modulate sensitivity to an AR signaling inhibitor enzalutamide that is often used for the treatment of castration-resistant prostate cancer. In AR-positive castration-resistant prostate cancer cell lines, aldosterone treatment significantly induced the cytotoxic effects of enzalutamide [35]. Correspondingly, MR knockdown via siRNA transfection in C4-2 prostate cancer cells resulted in considerable reduction in sensitivity to enzalutamide as well as enzalutamide-mediated apoptosis, although cell proliferation without enzalutamide treatment was similar between control-siRNA and MR-siRNA sublines [35].…”

“…In AR-positive castration-resistant prostate cancer cell lines, aldosterone treatment significantly induced the cytotoxic effects of enzalutamide [35]. Correspondingly, MR knockdown via siRNA transfection in C4-2 prostate cancer cells resulted in considerable reduction in sensitivity to enzalutamide as well as enzalutamide-mediated apoptosis, although cell proliferation without enzalutamide treatment was similar between control-siRNA and MR-siRNA sublines [35]. Interestingly, in this study [35], MR knockdown was also found to significantly increase the expression of AR gene and a downstream target prostate-specific antigen gene, suggesting potential interplay between MR and AR signals in prostate cancer cells.…”

Investigating the Role of Mineralocorticoid Receptor Signaling in Cancer Biology in the Genomic Era

“…However, prednisolone and aldosterone diminished resistance to enzalutamide. Consistently, silencing of MR resulted in enhanced resistance to enzalutamide and AR activity [55]. Moreover, the effects of diverse antihypertensive medication on prostate cancer survival following radical prostatectomy were tested in the Finnish population, and overall, the antihypertensive treatment was associated with increased death risk [56].…”

“…Enzalutamide is another antiandrogen drug used for treating metastatic prostate cancer patients; however, resistance gained against enzalutamide therapy remains a challenge. GR signaling induces antiandrogen resistance by hijacking AR function [53,54]; hence, the therapeutic effects of enzalutamide-corticosteroid coadministration were addressed in prostate cancer cells [55]. Dexamethasone decreased the therapeutic effects of enzalutamide as well as increasing resistance.…”