TGF-β signaling and androgen receptor status determine apoptotic cross-talk in human prostate cancer cells

BACKGROUND. A signaling interaction between transforming growth factor-β (TGF-β) and androgens promotes apoptosis in human prostate cancer cells LNCaP-TβRII (androgen-sensitive and TGF-β responsible). This study investigated the contribution of androgen receptor (AR) in the combined effect of TGF-β and dihydrotestosterone (DHT), on regulation of apoptosis and AR- and TGF-β mediated transcriptional activity in human prostate cancer cells. METHODS. Transcriptional activation in response to TGF-β (5 ng/ml) and DHT (1 nM) was evaluated using transient transfections and luciferase assays in human prostate cancer cells, LNCaP-TβRII and PC-3, overexpressing the wild type AR. The apoptotic response to DHT/TGFβ treatment was correlated with AR cellular distribution and the AR interaction with TGF-β intracellular effector Smad4. RESULTS. The results revealed that TGF-β signaling induced AR-mediated transcriptional activation in two androgen-responsive promoters [probasin and prostate specific antigen (PSA)]. TGF-β1 induced transcriptional activity enhanced by DHT in both cell lines (LNCaP-TβRII and PC-3-AR) via AR-Smad4 interaction. This interaction however does not exclusively drive TGF-β mediated apoptosis as DHT failed to enhance such an effect in PC-3 AR (wt) cells. CONCLUSIONS. These results demonstrate that the AR status determines the sensitivity of prostate cancer cells to the apoptotic effects of TGF-β1, thus providing a new insight into the mechanism via which TGF-β cross-sections the AR axis toward the functional convergence of the two pathways in the development of androgen-independent prostate cancer. This study is potentially significant in defining the contribution of AR status to the emergence of androgen-independent prostate tumors.