Requirement for NF-κB interleukin-4-induced androgen receptor activation in prostate cancer cells

BACKGROUND. Accumulating evidence suggest a critical role of activation of androgen receptor (AR) by nonandrogen in the development of androgen independent prostate cancer. Previous study identified that interleukin-4 (IL-4) enhances AR activation in the absence of androgen or in the very low levels of androgen in prostate cancer cells. In this study, the mechanism of IL-4-induced AR activation was investigated. METHODS & RESULTS. The induction of AR activation by IL-4 can be suppressed by expression of the IκBα, an inhibitor of NF-κB. The enhanced expression of AR-mediated prostate-specific antigen (PSA) by IL-4 was blocked by the expression of IκBα. IL-4 increases NF-κB transcriptional activity in prostate cancer cells which can be blocked by the addition of IL-4 antibody. IL-4 can also rapidly activate NF-κB. Furthermore, the IL-4-induced NF-κB activation and nuclear translocation can be blocked by LY294002, a PI3K/Akt specific inhibitor, suggesting that IL-4-induced NF-κB activation is mediated by activation of PI3K/Akt pathway. CONCULSION. In combination with previous study that IL-4 activates PI3K/Akt pathway, activation of PI3K/Akt > NF-κB pathways may be responsible for IL-4-induced AR activation in prostate cancer cells. Taken together, these studies suggest that IL-4 > PI3K/Akt > NF-κB signaling pathways, which activate AR signaling, may play an important role during the progression of androgen independent prostate cancer cells.