5alphaDH-DOC (5alpha-dihydro-deoxycorticosterone) activates androgen receptor in castration-resistant prostate cancer.
Prostate cancer often relapses during androgen-depletion therapy, even under the castration condition in which circulating androgens are drastically reduced. High expressions of androgen receptor (AR) and genes involved in androgen metabolism indicate a continued role for AR in castration-resistant prostate cancers (CRPCs). There is increasing evidence that some amounts of 5alpha-dihydrotestosterone (DHT) and other androgens are present sufficiently to activate AR within CRPC tissues, and enzymes involved in the androgen and steroid metabolism, such as 5alpha-steroid reductases, are activated in CRPCs. In this report, we screened eight natural 5alphaDH-steroids to search for novel products of 5alpha-steroid reductases, and identified 11-deoxycorticosterone (DOC) as a novel substrate for 5alpha-steroid reductases in CRPCs. 11-Deoxycorticosterone (DOC) and 5alpha-dihydro-deoxycorticosterone (5alphaDH-DOC) could promote prostate cancer cell proliferation through AR activation, and type 1 5alpha-steroid reductase (SRD5A1) could convert from DOC to 5alphaDH-DOC. Sensitive liquid chromatography-tandem mass spectrometric analysis detected 5alphaDH-DOC in some clinical CRPC tissues. These findings implicated that under an extremely low level of DHT, 5alphaDH-DOC and other products of 5alpha-steroid reductases within CRPC tissues might activate the AR pathway for prostate cancer cell proliferation and survival under castration.
Uemura
Motohide
M
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Honma
Seijiro
S
Chung
Suyoun
S
Takata
Ryo
R
Furihata
Mutsuo
M
Nishimura
Kazuo
K
Nonomura
Norio
N
Nasu
Yasutomo
Y
Miki
Tsuneharu
T
Shuin
Taro
T
Fujioka
Tomoaki
T
Okuyama
Akihiko
A
Nakamura
Yusuke
Y
Nakagawa
Hidewaki
H
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003900:Desoxycorticosterone / Q000494:pharmacology; D006801:Humans; D008297:Male; D009919:Orchiectomy; D011277:Pregnanediones / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D011944:Receptors, Androgen / Q000187:drug effects* / Q000502:physiology; D053719:Tandem Mass Spectrometry
D011277:Pregnanediones; D011944:Receptors, Androgen; D003900:Desoxycorticosterone; C084598:hydroxydione; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C476566:steroid-5alpha-reductase type 1