title: Dihydrotestosterone synthesis pathways from inactive androgen 5α-androstane-3β,17β-diol in prostate cancer cells: Inhibition of intratumoural 3β-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 5α-androstane-3β,17β-diol (3β-diol), which is inactive androgen metabolized from DHT. 3β-diol had biochemical potential to be converted to DHT via three metabolic pathways and could stimulate PC cell growth. Especially, 3β-diol was not only converted back to upstream androgens such as dehydroepiandrosterone (DHEA) or Δ5-androstenediol but also converted directly to DHT which is the main pathway from 3β-diol to DHT. Abiraterone had a significant influence on the metabolism of DHEA, epiandrosterone and 3β-diol, by the inhibition of the intratumoural 3β-hydroxysteroid dehydrogenase (3β-HSD) activities which is one of key catalysts in androgen metabolic pathway. The direct-conversion of 3β-diol to DHT was catalysed by 3β-HSD and abiraterone could inhibit this activity of 3β-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 3β-diol is important as one of the mechanisms of castration resistance in PC. Additionally, the inhibition of intratumoural 3β-HSD activity could be a new approach to castration-resistant prostate cancer treatment.
authors: Niigata University Graduate School of Medical and Dental Sciences, Department of Regenerative and Transplant Medicine, Niigata, 951-8510, Japan.
authors: Takashi
authors: T
authors: Ando
authors: Niigata University Graduate School of Medical and Dental Sciences, Department of Regenerative and Transplant Medicine, Niigata, 951-8510, Japan.
authors: Tsutomu
authors: T
authors: Nishiyama
authors: Niigata University Graduate School of Medical and Dental Sciences, Department of Regenerative and Transplant Medicine, Niigata, 951-8510, Japan.
authors: Itsuhiro
authors: I
authors: Takizawa
authors: Niigata University Graduate School of Medical and Dental Sciences, Department of Regenerative and Transplant Medicine, Niigata, 951-8510, Japan.
authors: Fumio
authors: F
authors: Ishizaki
authors: ASKA Pharmaceutical medical Co. Ltd., Kawasaki, 213-8522, Japan.
authors: Yoshimichi
authors: Y
authors: Miyashiro
authors: Niigata University Graduate School of Medical and Dental Sciences, Department of Regenerative and Transplant Medicine, Niigata, 951-8510, Japan.
authors: Keisuke
authors: K
authors: Takeda
authors: Niigata University Graduate School of Medical and Dental Sciences, Department of Regenerative and Transplant Medicine, Niigata, 951-8510, Japan.
authors: Noboru
authors: N
authors: Hara
authors: Niigata University Graduate School of Medical and Dental Sciences, Department of Regenerative and Transplant Medicine, Niigata, 951-8510, Japan.
authors: Yoshihiko
authors: Y
authors: Tomita
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015113:Androstane-3,17-diol / Q000378:metabolism*; D000736:Androstenes / Q000494:pharmacology*; D045744:Cell Line, Tumor; D013196:Dihydrotestosterone / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D000736:Androstenes; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D013196:Dihydrotestosterone; D015113:Androstane-3,17-diol; D015096:3-Hydroxysteroid Dehydrogenases; C089740:abiraterone