Document Detail

Antiandrogen effects of mifepristone on coactivator and corepressor interactions with the androgen receptor.
MedLine Citation:
PMID:  14593076     Owner:  NLM     Status:  MEDLINE    
Mifepristone is a potent antagonist of steroid hormone receptors such as glucocorticoid and progesterone receptors. We investigated the potential for mifepristone to act as an antiandrogen and compared it with partial androgen receptor (AR) agonists and antagonists, in particular bicalutamide. Mifepristone was an effective antiandrogen in vitro that inhibited transcription from three androgen-responsive promoters and blocked the agonist R1881 in a dose-dependent manner. Like bicalutamide, mifepristone also antagonized the action of androgen receptor with a (T877A) mutation. Mifepristone competed effectively with R1881 with a relative binding affinity comparable to that of cyproterone acetate, and much higher than that of hydroxyflutamide and bicalutamide in a binding assay. Mifepristone could effectively induce the binding of the herpes simplex viral protein 16/AR fusion protein to the hormone response elements in the murine mammary tumor virus-luciferase reporter. With either wild-type or T877A mutant AR, mifepristone alone was unable to induce any detectable interaction with coactivators transcriptional intermediary factor-2 or beta-catenin but could inhibit the R1881-induced binding of AR to transcriptional intermediary factor-2 and beta-catenin. Similarly, mifepristone could inhibit the R1881-induced N/C-terminal interaction in a dose-dependent manner even though mifepristone alone has no effect on the N/C-terminal interaction of AR. We found that mifepristone could induce a strong interaction between AR and corepressors nuclear receptor corepressor and silencing mediator for retinoid and thyroid hormone receptors in both transactivation and two-hybrid assays to a greater degree than hydroxyflutamide, cyproterone acetate, and bicalutamide. The AR-corepressor interaction was also seen in coimmunoprecipitation assays. Finally, mifepristone at high concentrations induced a low level of prostate-specific antigen expression in LNCaP and antagonized prostate-specific antigen expression induced by R1881. Mifepristone also antagonized R1881 action on the growth of LNCaP prostate cancer cells.
Liang-Nian Song; Meghan Coghlan; Edward P Gelmann
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.     Date:  2003-10-30
Journal Detail:
Title:  Molecular endocrinology (Baltimore, Md.)     Volume:  18     ISSN:  0888-8809     ISO Abbreviation:  Mol. Endocrinol.     Publication Date:  2004 Jan 
Date Detail:
Created Date:  2003-12-30     Completed Date:  2004-09-21     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  8801431     Medline TA:  Mol Endocrinol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  70-85     Citation Subset:  IM    
Department of Oncology, Lombardi Cancer Center, Georgetown University, 3800 Reservoir Road, Northwest, Washington, D.C. 20057, USA.
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MeSH Terms
Androgen Antagonists / pharmacology*
COS Cells
Cell Line
Cercopithecus aethiops
Genes, Reporter
Luciferases / analysis,  genetics
Mifepristone / pharmacology*
Mutagenesis, Site-Directed
Receptors, Androgen / drug effects,  genetics,  metabolism*
Recombinant Proteins / drug effects,  metabolism
Repressor Proteins / metabolism*
Grant Support
Reg. No./Substance:
0/Androgen Antagonists; 0/Receptors, Androgen; 0/Recombinant Proteins; 0/Repressor Proteins; 84371-65-3/Mifepristone; EC 1.13.12.-/Luciferases

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