Inhibition of p300/CBP expression in prostate cancer

The aim of endocrine therapy for advanced prostate cancer is to inhibit the levels of circulating androgen or interfere with androgen receptor (AR) function. This therapy is only palliative and all tumors will eventually relapse after endocrine treatment. Several mechanisms relevant to progression of prostate cancer were described in the literature. Transcriptional activation of the androgen receptor is enhanced through interaction with coactivator proteins. Evidence in the literature shows that transcriptional integrators p300 and CBP that are expressed in prostate cancer cell lines and clinical specimens are in part responsible for acquisition of agonistic effects of anti- androgens or AR activation by IL-6. The purpose of this translational project is to show that, on the basis of previously acquired results, reduced expression of these coactivators is an approach that may improve endocrine therapy. The following specific aims will be addressed: (a) which prostate cancer cell lines are most affected after inhibition of p300/CBP in vitro? (b) Does reduction of the levels of p300/CBP has any effect on cell motility and invasion? (c) What is the impact of down-regulation of p300/CBP on growth of prostate cancer in vivo? (d) Is there an effect of novel antiandrogen compounds on the expression of p300/CBP coactivators? The experiments will be performed in androgen-sensitive cell lines LNCaP and LAPC-4 as well as in androgen receptor-negative cells PC-3 and DU-145. The cells whose growth in vivo is strongly inhibited by the siRNA approach will be selected for further experiments. The results obtained in this project might lead to development of novel compounds that inhibit expression of the coactivators or interfere with there interaction with the AR.