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

Abstract

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 5alpha-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.

Phenothiazine Inhibitors of TLKs Affect Double-Strand Break Repair and DNA Damage Response Recovery and Potentiate Tumor Killing with Radiomimetic Therapy

“…11 The significance of the TLK-Rad9 axis is clear for CaP for which several studies have implicated Rad9's critical role in disease progression and prognosis. 41,42 Nonetheless, elevated Rad9 expression, and some of its phosphorylated forms, has been noted also in BCA and correlated to prognosis. 43 TLKs Are Targets for Therapeutic Intervention.…”

A Yeast Bioassay for Androgenic and Anti-Androgenic Compounds Based on the NH2- and COOH-Terminal Interaction of Androgen Receptor

“…1B), in agreement with previous results for mammalian cells. [3][4][5]10) Our results indicate that in yeast, the androgen-dependent N-C interaction is enhanced by certain coactivators. -Catenin is highly expressed in prostate cancer cells.…”

“…2) The binding of ligands to the LBD triggers intramolecular or intermolecular interaction between the NH 2 -and COOH-terminal regions (N-C interaction) of the AR. The N-C interaction is enhanced by certain coactivators including -catenin, 3) ARA24/Ran, 4) and p160 family proteins such as steroid receptor coactivator-1 (SRC-1) 5) and transcriptional intermediate factor-2 (TIF-2), 3) and is required for proper and maximal AR transactivation.…”

Chemopreventive Potential of an Ethyl Acetate Fraction from Curcuma Longa is Associated with Upregulation of p57kip2and Rad9 in the PC-3M Prostate Cancer Cell Line

“…The Rad9 gene has many functions that could bear on carcinogenesis, including a role in maintaining genome integrity and regulating cell cycle checkpoints (Lieberman et al, 1996;Bessho & Sancar, 2000;Komatsu et al, 2000;Hopkins et al, 2004;Aiping et al, 2008). Rad9 protein can bind AR and this protein-protein interaction represses the ability of testosterone to induce a conformational change in the receptor, to activate a receptor transcription regulatory function, and subsequently to express downstream target genes critical for proper prostate function Hsu et al, 2005;Lieberman, 2006). In our studies, PC-3M cells treated with ethyl acetate fraction both at 4 and 6µg/ml for 24 h showed significant up-regulation of about two fold higher the amount of both p57 kip2 and Rad9 genes when compared to corresponding controls (Figures 3).…”

“…It can bind and stimulate activity of several DNA repair proteins involved primarily in base excision repair (Lieberman, 2006). AR can bind human Rad9 and represses androgen-induced AR transcription activity in prostate cancer cells thus regulating prostate function Hsu et al, 2005). However, very little is known about the role of p57 kip2 and Rad9 during chemoprevention by turmeric and its derivatives especially in prostate cancer cell lines.…”