Most prostate cancer patients respond initially to androgen ablation and antiandrogen therapy. However, virtually all patients will relapse due to acquisition of the androgen-independent tumor cells. The molecular mechanisms characterizing prostate cancer progression from androgen-dependence to androgen-independence are incompletely understood. Androgen-independent activation of androgen receptor (AR) by cross-talk between AR and other signal pathways has been demonstrated to mediate prostate cancer androgen-independent progression in the absence of androgen. We previously demonstrated that overexpression of interleukin-6 (IL-6) is linked to prostate cancer progression accompanied by activation of Signal Transducers and Activators of Transcription 3 (Stat3) signaling. Further investigation in our laboratory demonstrated that Stat3 is constitutively activated in cells derived from both rat and human prostate cancers, and that Stat3 activation is correlated with malignant potential. In human prostate cancer cells, blockade of Stat3 expression suppressed proliferation in vitro and tumorigenicity in vivo. In addition, preliminary results demonstrate that the Stat3 signaling pathway interacts with the androgen receptor signaling pathway. Based on these results, we propose that Stat3 both regulates the expression of Stat3 target genes, and interacts with AR in prostate cancer cells. The experiments proposed in this application are based upon the hypothesis that Stat3 activation alters androgen receptor signaling pathway resulting in the loss of growth control in prostate cancer cells. Through our proposed analysis of the role of Stat3 activation in AR signaling in prostate cancer cells, we seek to provide a possible mechanism for the development of the androgen-independent prostate cancer cells. To accomplish this goal, we will examine the role of Stat3 activation in AR signaling in prostate cancer cells by establishing prostate cancer cell lines expressing constitutively activated Stat3 and examining the effect of Stat3 activation on androgen response in prostate cancer cells. We will then determine the molecular basis of interactions between Stat3 and the AR signaling. Finally, we will examine the association between Stat3 activation and prostate cancer progression.
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