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Androgen Receptor (AR) NH₂- and COOH-Terminal Interactions Result in the Differential Influences on the AR-Mediated Transactivation and Cell Growth

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 105, Taiwan; and Institute of Oral Medicine (Y.-L.C.), College of Medicine, National Cheng Kung University, Tainan 701, Taiwan

Address all correspondence and requests for reprints to: Chawnshang Chang, The George H. Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and the Cancer Center, University of Rochester Medical Center, Rochester, New York 14642. 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 5-dihydrotestosterone, but only the tested FXXLF-containing peptides, not FXXMF-containing peptides, can suppress prostate cancer CWR22R cell growth. Together, these results suggest that 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.

NURSA Molecule Pages Link:

Nuclear Receptors:   AR

Coregulators:   ARA54  |  ARA67  |  GSN  |  SRC-1  |  ARA70

Ligands:   Dihydrotestosterone

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