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Submitted on May 6, 2004
Accepted on October 19, 2004
The George H. Whipple Laboratory for Cancer Research (C.-L.H., Y.-L.C., H.-J.T., W.-J.L., Z.Y., Y.Z., L.W., C.-T.W., H.-C.C., S.Y.,C.C.), Departments of Pathology, Urology, Radiation Oncology, and the Cancer Center, University of Rochester Medical Center, Rochester, New York 14642; Institute of Pathology (S.W.P.), Case Western Reserve University, Cleveland, Ohio 44106; Division of Hematology-Oncology, Department of Internal Medicine (C.-L.H.), and Department of Urology (C.-T.W.), Chang Gung Memorial Hospital, Taipei, Taiwan; and Institute of Oral Medicine (Y.-L.C.), College of Medicine, National Cheng-Kung University, Tainan, Taiwan
* To whom correspondence should be addressed. E-mail: chang{at}URMC.rochester.edu.
Early reports showed that androgen receptor (AR) NH2- and COOH-terminal (N-C) interaction was important for full AR function. However, the influence of these interactions on the AR in vivo effects remains unclear. Here we tested some AR associated peptides and coregulators to determine their influences on AR N-C interaction, AR transactivation, and AR coregulator function. The results showed that AR coactivators such as ARA70N, gelsolin, ARA54, and SRC-1 can enhance AR transactivation, but showed differential influences on the N-C interaction. In contrast, AR corepressors ARA67 and Rad9 can suppress AR transactivation, with ARA67 enhancing and Rad9 suppressing AR N-C interaction. Furthermore, liganded AR C-terminus associated peptides can block AR N-C interaction, but only selective peptides can block AR transactivation and coregulator function. We found all the tested peptides can suppress prostate cancer LNCaP cell growth at different levels in the presence of DHT, but only the tested FXXLF-containing peptides, but not FXXMF-containing peptides can suppress prostate cancer CWR22R cell growth. Together, these results suggest the effects of AR N-C interactions may not always correlate with similar effects on AR-mediated transactivation and/or AR-mediated cell growth. Therefore, drugs designed by targeting AR N-C interaction as a therapeutic intervention for prostate cancer treatment may face unpredictable in vivo effects.
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