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5alphaDH-DOC (5alpha-dihydro-deoxycorticosterone) activates androgen receptor in castration-resistant prostate cancer.
- Source :
-
Cancer science [Cancer Sci] 2010 Aug; Vol. 101 (8), pp. 1897-904. Date of Electronic Publication: 2010 May 17. - Publication Year :
- 2010
-
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.
- Subjects :
- 3-Oxo-5-alpha-Steroid 4-Dehydrogenase physiology
Cell Line, Tumor
Cell Proliferation drug effects
Desoxycorticosterone pharmacology
Humans
Male
Orchiectomy
Pregnanediones analysis
Pregnanediones metabolism
Prostatic Neoplasms drug therapy
Receptors, Androgen physiology
Tandem Mass Spectrometry
Pregnanediones pharmacology
Prostatic Neoplasms pathology
Receptors, Androgen drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1349-7006
- Volume :
- 101
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Cancer science
- Publication Type :
- Academic Journal
- Accession number :
- 20560974
- Full Text :
- https://doi.org/10.1111/j.1349-7006.2010.01620.x