5αDH-DOC (5α-dihydro-deoxycorticosterone) activates androgen receptor in castration-resistant prostate cancer

Motohide Uemura, Seijiro Honma, Suyoun Chung, Ryo Takata, Mutsuo Furihata, Kazuo Nishimura, Norio Nonomura, Yasutomo Nasu, Tsuneharu Miki, Taro Shuin, Tomoaki Fujioka, Akihiko Okuyama, Yusuke Nakamura, Hidewaki Nakagawa

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14 Citations (Scopus)

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 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).

Original languageEnglish
Pages (from-to)1897-1904
Number of pages8
JournalCancer Science
Volume101
Issue number8
DOIs
Publication statusPublished - Aug 1 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Uemura, M., Honma, S., Chung, S., Takata, R., Furihata, M., Nishimura, K., Nonomura, N., Nasu, Y., Miki, T., Shuin, T., Fujioka, T., Okuyama, A., Nakamura, Y., & Nakagawa, H. (2010). 5αDH-DOC (5α-dihydro-deoxycorticosterone) activates androgen receptor in castration-resistant prostate cancer. Cancer Science, 101(8), 1897-1904. https://doi.org/10.1111/j.1349-7006.2010.01620.x