title: Androgen deprivation promotes intratumoral synthesis of dihydrotestosterone from androgen metabolites in prostate cancer.
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.
authors.affiliation: Division of Urology, Department of Regenerative and Transplant Medicine, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Ishizaki
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nishiyama
authors.forename: Takashi
authors.initials: T
authors.lastname: Kawasaki
authors.forename: Yoshimichi
authors.initials: Y
authors.lastname: Miyashiro
authors.forename: Noboru
authors.initials: N
authors.lastname: Hara
authors.forename: Itsuhiro
authors.initials: I
authors.lastname: Takizawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Naito
authors.forename: Kota
authors.initials: K
authors.lastname: Takahashi
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D000368:Aged; D000728:Androgens / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D015113:Androstane-3,17-diol / Q000378:metabolism*; D045744:Cell Line, Tumor; D003687:Dehydroepiandrosterone / Q000378:metabolism; D013196:Dihydrotestosterone / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering
chemical_list: D000728:Androgens; D034741:RNA, Small Interfering; D013196:Dihydrotestosterone; D015113:Androstane-3,17-diol; D003687:Dehydroepiandrosterone; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase