JunD Is Required for Proliferation of Prostate Cancer Cells and Plays a Role in Transforming Growth Factor-β (TGF-β)-induced Inhibition of Cell Proliferation.

Abstract Transforming growth factor-β (TGF-β) inhibits proliferation of prostate epithelial cells. However, prostate cancer cells in advanced stages become resistant to inhibitory effects of TGF-β. The intracellular signaling mechanisms involved in differential effects of TGF-β during different stages are largely unknown. Using cell line models, we have shown that TGF-β inhibits proliferation in normal (RWPE-1) and prostate cancer (DU145) cells, but does not have any effect on proliferation of prostate cancer (PC3) cells. We have investigated the role of Jun family of proteins (c-Jun, JunB and JunD) in TGF-β1 effects on cell proliferation. Jun family members were expressed at different levels and responded differentially to TGF-β treatment. TGF-β effects on JunD protein levels, but not mRNA levels, correlated with its effects on cell proliferation. TGF-β induced significant reduction in JunD protein in RWPE-1 and DU145 cells, but not in PC3 cells. Selective knock-down of JunD expression using siRNA in DU145 and PC3 cells resulted in significant reduction in cell proliferation, and forced overexpression of JunD increased proliferation rate. On the other hand, knock-down of c-Jun or JunB had little, if any, effect on cell proliferation; over-expression of c-Jun and JunB decreased proliferation rate in DU145 cells. Further studies showed that down-regulation of JunD in response to TGF-β treatment is mediated via proteasomal degradation pathway. In conclusion, we show that specific Jun family members exert differential effects on proliferation in prostate cancer cells in response to TGF-β, and inhibition of cell proliferation by TGF-β requires degradation of JunD protein.