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5alphaDH-DOC (5alpha-dihydro-deoxycorticosterone) activates androgen receptor in castration-resistant prostate cancer.

Authors
  • Uemura, Motohide
  • Honma, Seijiro
  • Chung, Suyoun
  • Takata, Ryo
  • Furihata, Mutsuo
  • Nishimura, Kazuo
  • Nonomura, Norio
  • Nasu, Yasutomo
  • Miki, Tsuneharu
  • Shuin, Taro
  • Fujioka, Tomoaki
  • Okuyama, Akihiko
  • Nakamura, Yusuke
  • Nakagawa, Hidewaki
Type
Published Article
Journal
Cancer science
Publication Date
Aug 01, 2010
Volume
101
Issue
8
Pages
1897–1904
Identifiers
DOI: 10.1111/j.1349-7006.2010.01620.x
PMID: 20560974
Source
Medline
License
Unknown

Abstract

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.

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