Interleukin-6 Undergoes Transition To Autocrine Differentiation And Increases Prostate Cancer Cells Resistance To Bicalutamide Via TIF2

BACKGROUND. The standard treatment for advanced, androgen-responsive prostate cancer is androgen deprivation therapy with or without a nonsteroidal antiandrogen, such as bicalutamide. Although maximal androgen blockade exhibits favorable responses in the majority of patients, prostate cancer eventually progresses to an androgen-refractory stage. The mechanism underlying bicalutamide resistance in the course of prostate cancer progression is incompletely understood. However, interleukin-6 (IL-6) plays a critical role in the development and progression of CRPC.Herein, we explored an association between IL-6 and bicalutamide resistance.METHODS. Series of lower and higher passages of LNCaP cell sublines were generated by a long-term exposure ofLNCaPcells in IL-6-containing culture media. The characteristics of these cell sublines were analyzed and the potential roles of neuroendocrine differentiation and androgen receptor activation were examined.RESULTS. We demonstrated that while short-term treatment of IL-6 inhibits LNCaP cell growth by a paracrine mechanism associated with NE differentiation, long-term treatment of IL-6 promotes LNCaP cell growth by an autocrine mechanism accompanied by an activation of AR signaling. To study this, series of lower and higher passages of LNCaPcell sublines generated by long-term exposure to IL-6 were used. The cells from higher passages of LNCaPtreated with IL-6 developed resistance to bicalutamide treatment compared with parental LNCaPcells. The levels of transcriptional intermediary factor 2 (TIF2) in IL-6-treated LNCaPcells were found to be significantly higher than parental LNCaP cells. Down-regulation of TIF2 expression via short hairpin RNA in IL-6-treated LNCaPcells sensitized these cells to bicalutamide treatment, whereas overexpression of TIF2 in the parental LNCaPcells increased resistance to bicalutamide. Furthermore, overexpression of IL-6 attenuated bicalutamide-mediated blockage of androgen-induced androgen receptor nuclear translocation and recruitment.CONCLUSIONS. These studies suggest that acquisition of endogenous IL-6 production after prolong exposure of prostate cancer cells to IL-6 may contribute to an autocrine cell growth stimulation, Overexpression of IL-6 increases the resistance of prostate cancer cells to bicalutamide via TIF2. Overexpression of IL-6 not only plays an important role in prostate cancer progression but also contributes to bicalutamide resistance. Our studies suggest that bicalutamide- IL-6-targeted adjunctive therapy may lead to a more effective intervention than bicalutamide alone.