Promotion of agonist activity of antiandrogens by the androgen receptor coactivator, ARA70, in human prostate cancer DU145 cells.
Although hormone therapy with antiandrogens has been widely used for the treatment of prostate cancer, some antiandrogens may act as androgen receptor (AR) agonists that may result in antiandrogen withdrawal syndrome. The molecular mechanism of this agonist response, however, remains unclear. Using mammalian two-hybrid assay, we report that antiandrogens, hydroxyflutamide, bicalutamide (casodex), cyproterone acetate, and RU58841, and other compounds such as genistein and RU486, can promote the interaction between AR and its coactivator, ARA70, in a dose-dependent manner. The chloramphenicol acetyltransferase assay further demonstrates that these antiandrogens and related compounds significantly enhance the AR transcriptional activity by cotransfection of AR and ARA70 in a 1:3 ratio into human prostate cancer DU145 cells. Our results suggest that the agonist activity of antiandrogens might occur with the proper interaction of AR and ARA70 in DU145 cells. These findings may provide a good model to develop better antiandrogens without agonist activity.
Miyamoto
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H
George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, and Biochemistry, University of Rochester Medical Center, Rochester, NY 14642, USA.
Yeh
S
S
Wilding
G
G
Chang
C
C
D000726:Androgen Antagonists / Q000378:metabolism*; D000728:Androgens; D000813:Anilides / Q000378:metabolism; D017373:Cyproterone Acetate / Q000378:metabolism; D004347:Drug Interactions; D005485:Flutamide / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000378:metabolism; D008297:Male; D015735:Mifepristone / Q000378:metabolism; D009570:Nitriles / Q000378:metabolism; D056918:Nuclear Receptor Coactivators; D015513:Oncogene Proteins; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D014105:Tosyl Compounds; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D000726:Androgen Antagonists; D000728:Androgens; D000813:Anilides; D007093:Imidazoles; C111382:NCOA4 protein, human; D009570:Nitriles; D056918:Nuclear Receptor Coactivators; D015513:Oncogene Proteins; D014105:Tosyl Compounds; D015534:Trans-Activators; D014157:Transcription Factors; C086458:RU 58841; C014290:hydroxyflutamide; D015735:Mifepristone; D017373:Cyproterone Acetate; D005485:Flutamide; C053541:bicalutamide