Dihydrotestosterone synthesis pathways from inactive androgen 5?-androstane-3?,17?-diol in prostate cancer cells: Inhibition of intratumoural 3?-hydroxysteroid dehydrogenase activities by abiraterone.

ABSTRACT: Intratumoural dihydrotestosterone (DHT) synthesis could be an explanation for castration resistance in prostate cancer (PC). By using liquid chromatography-mass spectrometry, we evaluated the intratumoral DHT synthesis from 5?-androstane-3?,17?-diol (3?-diol), which is inactive androgen metabolized from DHT. 3?-diol had biochemical potential to be converted to DHT via three metabolic pathways and could stimulate PC cell growth. Especially, 3?-diol was not only converted back to upstream androgens such as dehydroepiandrosterone (DHEA) or ?5-androstenediol but also converted directly to DHT which is the main pathway from 3?-diol to DHT. Abiraterone had a significant influence on the metabolism of DHEA, epiandrosterone and 3?-diol, by the inhibition of the intratumoural 3?-hydroxysteroid dehydrogenase (3?-HSD) activities which is one of key catalysts in androgen metabolic pathway. The direct-conversion of 3?-diol to DHT was catalysed by 3?-HSD and abiraterone could inhibit this activity of 3?-HSD. These results suggest that PC had a mechanism of intratumoural androgen metabolism to return inactive androgen to active androgen and intratumoural DHT synthesis from 3?-diol is important as one of the mechanisms of castration resistance in PC. Additionally, the inhibition of intratumoural 3?-HSD activity could be a new approach to castration-resistant prostate cancer treatment.

SUBMITTER: Ando T 

PROVIDER: S-EPMC4999866 | biostudies-other | 2016

REPOSITORIES: biostudies-other