Androgen deprivation promotes intratumoral synthesis of dihydrotestosterone from androgen metabolites in prostate cancer.

Intratumoral synthesis of dihydrotestosterone (DHT) from precursors cannot completely explain the castration resistance of prostate cancer. We showed that DHT was intratumorally synthesized from the inactive androgen metabolites 5α-androstane-3α/β,17β-diol (3α/β-diol) in prostate cancer cells via different pathways in a concentration-dependent manner. Additionally, long-term culture in androgen-deprived media increased transcriptomic expression of 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), a key enzyme of oxidative 3α-HSD that catalyzes the conversion of 3α-diol to DHT in prostate cancer cells. Correspondingly, the score for HSD17B6 in tissues of 42 prostate cancer patients undergoing androgen deprivation therapy (ADT) was about 2-fold higher than that in tissues of 100 untreated individuals. In men receiving ADT, patients showing biochemical progression had a higher HSD17B6 score than those without progression. These results suggested that 3α/β-diol also represent potential precursors of DHT, and the back conversion of DHT from androgen derivatives can be a promising target for combination hormone therapy.