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

Sci Rep. 2013;3:1528. doi: 10.1038/srep01528.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 17-Hydroxysteroid Dehydrogenases / genetics
  • 17-Hydroxysteroid Dehydrogenases / metabolism*
  • Aged
  • Androgens / chemistry
  • Androgens / deficiency
  • Androgens / metabolism*
  • Androstane-3,17-diol / metabolism*
  • Cell Line, Tumor
  • Dehydroepiandrosterone / metabolism
  • Dihydrotestosterone / metabolism*
  • Humans
  • Male
  • Middle Aged
  • Prostatic Neoplasms / enzymology
  • Prostatic Neoplasms / metabolism*
  • RNA Interference
  • RNA, Small Interfering

Substances

  • Androgens
  • RNA, Small Interfering
  • Dihydrotestosterone
  • Androstane-3,17-diol
  • Dehydroepiandrosterone
  • 17-Hydroxysteroid Dehydrogenases
  • 3 (or 17)-beta-hydroxysteroid dehydrogenase