TY - JOUR
T1 - 5αDH-DOC (5α-dihydro-deoxycorticosterone) activates androgen receptor in castration-resistant prostate cancer
AU - Uemura, Motohide
AU - Honma, Seijiro
AU - Chung, Suyoun
AU - Takata, Ryo
AU - Furihata, Mutsuo
AU - Nishimura, Kazuo
AU - Nonomura, Norio
AU - Nasu, Yasutomo
AU - Miki, Tsuneharu
AU - Shuin, Taro
AU - Fujioka, Tomoaki
AU - Okuyama, Akihiko
AU - Nakamura, Yusuke
AU - Nakagawa, Hidewaki
N1 - Copyright:
Copyright 2010 Elsevier B.V., All rights reserved.
PY - 2010/8
Y1 - 2010/8
N2 - 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).
AB - 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).
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U2 - 10.1111/j.1349-7006.2010.01620.x
DO - 10.1111/j.1349-7006.2010.01620.x
M3 - Article
C2 - 20560974
AN - SCOPUS:77954847434
SN - 1347-9032
VL - 101
SP - 1897
EP - 1904
JO - Cancer Science
JF - Cancer Science
IS - 8
ER -
