Inactivation of androgen receptor coregulator ARA55 inhibits androgen receptor activity and agonist effect of antiandrogens in prostate cancer cells.
Antiandrogens given to antagonize androgen receptor (AR) activity gradually lose their efficacy as antagonists and eventually function as agonists to promote (instead of block) AR-mediated growth of prostate cancer cells. The mechanisms of how antiandrogens acquire this agonist activity during hormonal therapy are largely unknown. Here, we report that expression of a dominant-negative AR-associated protein 55 (dARA55) coregulator, inhibits AR transcriptional activity and reduces the agonist activity of antiandrogens. Inducibly expressed dARA55 inhibits prostate-specific antigen and cell growth in prostate cancer cells. Further dissection of the molecular mechanism shows dARA55 can selectively suppress endogenous AR-associated protein 55 (ARA55) enhanced AR transactivation by means of interruption of dimerization between ARA55 and ARA55. These results were confirmed by using RNA interference-mediated silencing of the ARA55 gene. These results therefore provide evidence that AR function could be suppressed without mutation or change in AR itself. Taken together, these findings not only demonstrate the important roles of the ARA55 coregulator in the AR-mediated growth of prostate cancer, they also may provide a critical target for developing therapeutic agents for the antiandrogen therapy that almost always fails in the treatment of hormone-refractory prostate cancer.
Rahman
Mujib M
MM
George Whipple Laboratory for Cancer Research, Department of Biochemistry, and the Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
Miyamoto
Hiroshi
H
Lardy
Henry
H
Chang
Chawnshang
C
D000726:Androgen Antagonists / Q000378:metabolism*; D059002:Androgen Receptor Antagonists; D000728:Androgens; D001483:Base Sequence; D015153:Blotting, Western; D017931:DNA Primers; D020868:Gene Silencing; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000235:genetics; D014407:Tumor Cells, Cultured; D020798:Two-Hybrid System Techniques
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000728:Androgens; D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; C490351:TGFB1I1 protein, human; D015534:Trans-Activators