Aldosterone mediates a mineralocorticoid receptor‐mediated increase in prostate cancer cell migration

Abstract

Aldosterone is a well‐established regulator of renal and cardiovascular functions. However, its role in regulation of cancer growth and spread has only begun to be appreciated. Studies from our laboratory have demonstrated that aldosterone stimulates renal cancer cell migration in vitro and metastatic spread in vivo (Feldman et. al. FASEB J. 2016 30(6)2086–96). However, the generalizability of these findings to other cancers is unknown. Therefore, we assessed the effect of aldosterone on prostate cancer cell migration and the receptor mechanism involved utilizing three widely‐used prostate cancer cell lines, viz. TRAMP C1, LNCaP and DU 145 cells.RT‐PCR analysis detected robust expression of the mineralocorticoid receptor (MR) in all cell lines. GPER expression was detectable in TRAMP C1 and LNCaP cells but not in DU145 cells. In LNCaP and TRAMPC1 cells, aldosterone mediated a concentration‐dependent increase in migration to a maximum of 141±7% of control at 1000 nM (n=5) in LNCaP cells and 125±3 % at 10 nM (n=6) in TRAMP C1 cells, similar to the maximal extent of stimulation by testosterone [146±9% (n=9) in LNCaP cells and 136±9% (n=3) in TRAMP C1 cells]. The effects of aldosterone were inhibited by the MR antagonist eplerenone, but NOT by the GPER antagonist G15. In contrast, the GPER agonist, G1, INHIBITED migration in both cell lines‐effects that were blocked by G15. In DU 145, cells neither testosterone nor aldosterone stimulated migration.In TRAMP C1 cells, infection with an adeno shMR vector blocked aldosterone‐mediated stimulation of proliferation/migration without effects on G1‐mediated inhibition, whereas infection with an adeno shGPER vector selectively blocked G1‐mediated inhibition of proliferation and migration, without effects on aldosterone’s actions.These findings suggest that in TRAMP C1 and LNCaP cells aldosterone stimulates migration via an MR‐dependent pathway. In DU145 cells, resistance to the effect of aldosterone paralleled resistance to the effect of testosterone. These data support the hypothesis that inhibiting aldosterone secretion/effects may be a novel adjunctive therapeutic approach‐‐at least in some forms of prostate cancer.Support or Funding InformationHeart and Stroke Foundation of Canadaand Molson Foundation