Interleukin-6 induces androgen responsiveness in prostate cancer cells through up-regulation of androgen receptor expression

Interleukin-6 (IL-6) induces prostate cancer (CaP) cell proliferation ill v itro, Several lines of evidence suggest that IL-6 may promote CaP progressi on through induction of an androgen response. In this work, we explored whe ther IL-6 induces androgen responsiveness through modulation of androgen re ceptor (AR) expression. We found that in the absence of androgen, IL-6 incr eased prostate-specific antigen (PSA) mRNA levels and activated several and rogen-responsive promoters, but not the non-androgen responsive promoters i n LNCaP cells, Bicalutamide, an antiandrogen, abolished the IL-6 effect and IL-6 could not activate the PSA and murine mammary tumor virus reporters i n AR-negative DU-145 and PC3 cells. These data indicate the IL-6 induces an androgen response in CaP cells through the AR. Pretreatment of LNCaP cells with SB202190, PD98059, or tyrphostin AG879 [p38 mitogen-activated protein kinase (MAPK), MAP/extracellular signal-regulated protein kinase kinase 1/ 2, and ErbB2 MAPK inhibitors, respectively) but not wortmannin (PI3-kinase inhibitor) blocked IL-6-mediated induction of the PSA promoter, which demon strates that IL-6 activity is dependent on a MARK pathway. Finally, IL-6 ac tivated the AX gene promoter, resulting in increased AR mRNA and protein le vels in LNCaP cells. These results demonstrate that IL-6 induces AR express ion and are the first report of cytokine-mediated induction of the AR promo ter, Taken together, our results suggest that IL-6 induces AR activity thro ugh both increasing AR gene expression and activating the AR in the absence of androgen in CaP cells. These results provide a mechanism through which IL-6 may contribute to the development of androgen-independent CaP.