Open Access5αDH‐DOC (5α‐dihydro‐deoxycorticosterone) activates androgen receptor in castration‐resistant prostate cancer
Author(s) -
Uemura Motohide,
Honma Seijiro,
Chung Suyoun,
Takata Ryo,
Furihata Mutsuo,
Nishimura Kazuo,
omura Norio,
Nasu Yasutomo,
Miki Tsuneharu,
Shuin Taro,
Fujioka Tomoaki,
Okuyama Akihiko,
Nakamura Yusuke,
Nakagawa Hidewaki
Publication year - 2010
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2010.01620.x
Subject(s) - prostate cancer , androgen receptor , dihydrotestosterone , androgen , steroid , endocrinology , medicine , castration , chemistry , cancer research , biology , cancer , hormone
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 5α‐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 5α‐steroid reductases, are activated in CRPCs. In this report, we screened eight natural 5αDH‐steroids to search for novel products of 5α‐steroid reductases, and identified 11‐deoxycorticosterone (DOC) as a novel substrate for 5α‐steroid reductases in CRPCs. 11‐Deoxycorticosterone (DOC) and 5α‐dihydro‐deoxycorticosterone (5αDH‐DOC) could promote prostate cancer cell proliferation through AR activation, and type 1 5α‐steroid reductase (SRD5A1) could convert from DOC to 5αDH‐DOC. Sensitive liquid chromatography‐tandem mass spectrometric analysis detected 5αDH‐DOC in some clinical CRPC tissues. These findings implicated that under an extremely low level of DHT, 5αDH‐DOC and other products of 5α‐steroid reductases within CRPC tissues might activate the AR pathway for prostate cancer cell proliferation and survival under castration. ( Cancer Sci 2010)