Endothelin-1 induces changes in the expression levels of steroidogenic enzymes and increases androgen receptor and testosterone production in the PC3 prostate cancer cell line

Abstract

Endothelin-1 (ET-1) is involved in the regulation of steroidogenesis. Additionally, patients with castration-resistant prostate cancer (PCa) have a higher ET-1 plasma concentration than those with localized PCa and healthy individuals. The aim of the present study was to evaluate the effect of ET-1 on steroidogenesis enzymes, androgen receptor (AR) and testosterone (T) production in PCa cells. The expression levels of endothelin receptors in prostate tissue from patients with localized PCa by immunohistochemistry, and those in LNCaP and PC3 cells were determined reverse transcription-quantitative PCR (RT-qPCR) and western blotting. Furthermore, the expression levels of ET-1 were determined in LNCaP and PC3 cells by RT-qPCR and western blotting. The ET-1 receptor activation was evaluated by intracellular calcium measurement, the expression levels of AR and enzymes participating in steroidogenesis [cytochrome P450 family 11 subfamily A member 1 (CyP11A1), cytochrome P450 family 17 subfamily A member 1, aldo-keto reductase family member C2 and 3 beta-hydroxysteroid dehydrogenase/isomerase 2 (3 beta HSD2)] were determined by western blotting and T concentration was determined by ELISA using PC3 cells. The present results revealed higher expression levels of endothelin A receptor (ETAR) in tissues obtained from samples of patients with PCa with a low Gleason Score. No changes were identified for endothelin B receptor (ETBR). PC3 cells expressed higher levels of ET-1 and ETAR, while LNCaP cells exhibited higher expression levels of ETBR. Blocking of ETAR and endothelin B receptor decreased the expression levels of CyP11A1 and 3 beta HSD2 enzymes and AR in PC3 cells, as well as T secretion. These findings suggested that ET-1 has a potential role in modulating the intratumoral steroidogenesis pathway and might have relevance as a possible therapeutic target.