Almost all prostate cancer (PCa) patients who receive androgen ablation therapy will relapse with hormone refractory prostate cancer (HRPC) and eventual bone metastatic disease, for which there is limited or no curative therapy. The majority of HRPC and bone metastatic disease are still androgen receptor (AR) positive but do not respond to therapy due to promiscuous activity of AR together with the activation of Akt/NF-xB signaling among others. Therefore, there is a dire need for the development of novel non-toxic strategies by which AR itself could be inactivated and thereby growth response via AR signaling could be destroyed in order to make an impact in the prevention and treatment of HRPC, which is the main focus of this application. We found that pure genistein as well as soy isoflavone down-regulates AR, PSA, Akt, NF-KB and their target genes (especially MMP-9, uPA, Cox-2 and VEGF which are known to promote invasion and angiogenesis) and induce apoptotic cell death of PCa cell lines but not normal prostate epithelial cells. Moreover, we found that pure genistein increased lymph node metastasis in an orthotopic model of PCa, however such an adverse effect was not observed with soy isoflavone. Based on our progress report and our preliminary results, we hypothesize that soy isoflavone will function as an inhibitor of AR signaling directly or indirectly due to the inactivation of Akt/NF-KB, ultimately causing cell growth inhibition and induction of apoptosis. We further hypothesize that soy isoflavone will inhibit tumor growth in animals and that the exposure of tumors to isoflavone in vivo will result in the down regulation of genes downstream of AR signaling leading to chemo-sensitization to Taxotere (a common chemotherapeutic agent). To test our hypotheses, we designed four specific aims using four relevant PCa cell lines containing wild-type and mutant AR, especially LNCaP derived C4-2B cells that are more akin to HRPC and bone metastasis, to answer the following questions: (a) How is AR down regulated by soy isoflavone and what is the molecular mechanism? (b) What is the cellular consequence of the down regulation of AR? (c) Is this down regulation associated with molecular regulation of NF-KB, RANK, RANKL, MMP-9, uPA, Cox-2 and VEGF and, in turn, results in the inhibition of tumor growth, angiogenesis, invasion and metastasis in an experimental animal model in vivo? (d) Could anti-tumor effects be correlated with inactivation of AR and NF-KB regulated genes, especially MMP-9, uPA, Cox-2 and VEGF in vivo?, and finally (e) Does inactivation of AR cause chemo- sensitization of prostate cancer cells to Taxotere in vitro and in vivo? Understanding of the molecular and cellular mechanism by which isoflavone inactivates AR signaling and, in combination with Taxotere, stops tumor growth in animal models will have a significant impact in the management of patients diagnosed with HRPC and bone metastasis for which there is no curative therapy. ? ? ?
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