The androgen-signaling pathway plays a critical role in the regulation of prostate cancer cell growth and survival. Consequently, androgen ablation has been used as an effective treatment for the majority of advanced prostate cancers. Androgen receptor (AR), like other members of the steroid receptor superfamily, functions as a ligand-activated transcription factor, controlling the expression of genes involved in cell proliferation, migration, differentiation and death. Increasing cellular level of AR not only intensify androgen-induced cell proliferation but also increases the sensitivity of prostate cancer cells to androgens, allowing tumor cells to grow and migrate in a low androgen environment.

To understand whether and how the AR is critical in prostate carcinogenesis, we used siRNA constructs to observe the AR's effect on androgen-induced transcription, cell proliferation and migration. Three AR siRNA constructs that contained 21-mer sequences derived from different coding regions of the human AR (AMBION) all showed specific silencing of AR expression. Treatment of LNCaP cells with siRNA for AR significantly reduced the expression of prostatic cancer markers as prostate specific antigen and prostatic acid phospatase. RT-PCR, immunoprecipitation and Western blot analysis were used to observe possible interaction of the androgen receptor with beta-catenin in prostate cancer cells and AR’s function in beta-catenin pathway. The high expression of beta-catenin and over expression of prostatic markers was significantly associated with progression of carcinogenesis and demonstrated a dose- and time-dependence on steroid hormones (testosterone, DHT, estradiol). Free unphosphorylated beta-catenin was translocated into the nucleus what was accompanied by increased cell migration as well as proliferation in androgen dependent cancer cell line (Boyden chamber; Cell proliferation, ELISA, BrdU; Violet crystal). Simultaneously phospho-beta catenin (ser33/37/Thr41 and thr41/Ser45) blocking peptides (Cell Signaling) were applied to confirm unphosphorylated and phosphorylated level of beta-catenin after treatment the cells with androgen after the use siRNA for AR.

Based on the studies on AR-expressing cells (LNCaP) and non-AR-expressing cells (PC3, Du145) we postulate that the AR can have an effect on passage of the beta-catenin into the nucleus when exposed to exogenous androgen. These observation suggest the role of beta-catenin in the regulation of AR function and its role in prostate cancer progression.

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