ANAHEIM, CA (UroToday.com) - Lynn Xue and researchers at the University of California, Davis presented “Prolonged Androgen Receptor Occupancy at the PSA Promoter Occurs in Androgen-Independent Cells” (ABST#543 - Prostate Cancer Basic Research III) . They sought to determine how the AR contributes to the proliferation of androgen-independent (AI) cells. The purpose of the study was to determine whether a prolonged association of AR with the PSA promoter occurs in AI cells. To do this androgen-dependent (AD) LNCaP cells and its AI subline (LNCaP-cds2) were treated with different ligands. A chromatin-immunoprecipitation (ChIP) assay was used to examine the binding of the AR to the PSA promoter, while a ChIP-Western blot assay was used to assess the recruitment of p160 coactivators (SRC1 and TIF2) to the AR-ARE complex. The expression of AR and its p160 coactivators was detected using Western blot assay, and their association was determined using immunoprecipitation (IP).

Treatment of LNCaP cells with synthetic androgen R1881 resulted in rapid loading of the AR onto the ARE III region of PSA promoter. AR occupancy on the promoter was a cyclic kinetic event. In contrast, in AI cells, AR highly occupies the ARE III region without showing cyclic occupancy. Instead of blocking the association of AR and ARE in LNCaP cells, the androgenic antagonist, Casodex, stimulated the binding of AR to the ARE. When compared with AD cells, AI cells increased the expression of AR and coactivators, as well as increased AR-coactivator association and recruitment of coactivators to the AR-ARE complex. This data demonstrates that in AI cells AR exhibits a prolonged occupying time on the PSA promoter and increased recruitment of coactivators to the AR-ARE complex. Since AR blockade stimulates the proliferation of AI CaP cells, down-regulation of the expression of AR and/or its coactivator may represent novel strategies for treatment of AI CaP.

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Written by Christopher P. Evans, MD, a Contributing Editor with UroToday.

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