The majority of prostate cancer (PCa) patients treated with hormone ablation therapy develop hormone refractory prostate cancer (HRPC), and leads to predominant bone metastatic disease that still contains Akt- activated functional androgen receptor (AR), and for which there is no curative therapy. In HRPC (also known as castrate resistant tumors) and bone metastatic disease, AR functions promiscuously, at least, due to the activation of Akt signaling. Therefore it is important to understand how Akt activates AR, and most importantly develop a non-toxic strategy by which AR in PCa could be totally inactivated;thereby growth response via AR signaling could be totally destroyed. Previous studies have shown that consumption of fruits and vegetables provides indole compounds [indole-3-carbinol (I3C) and its in vivo product 3-3'-diindolylmethane (DIM)] that are believed to be protective against the development of human PCa. Our studies during the preceding funding period showed that DIM and a well-standardized formulated DIM obtained from BioResponse, named BR-DIM (hereafter referred as B-DIM), down-regulated Akt, NF-:B, AR, 2-catenin and PSA, and induced apoptotic cell death of PCa cell lines but not normal prostate epithelial cells. Moreover, we have shown that DIM could inhibit invasion and angiogenesis. Based on our preliminary results and the existing knowledge on Akt/Wnt/AR signaling, we hypothesize that 2-catenin is a critical molecule for the signal transduction between Akt, Wnt, and AR signaling network and that the use of B-DIM will serve as a novel approach by which the progression, invasion, and metastasis of PCa could be inhibited through the regulation of 2-catenin mediated Akt/Wnt/AR signaling. We further hypothesize that B-DIM will elicit anti-tumor activity in animal model and that B-DIM could be targeted to human prostate gland in PCa patient. To test our hypotheses, we designed four specific aims where androgen sensitive (LNCaP, mutant AR+) and androgen insensitive (LNCaP derived C4- 2B and CWR22Rv1, mutant AR+) cells will be used to answer the following questions: (a) how Akt regulates Wnt signaling via 2-catenin pathway, (b) how 2-catenin regulates AR signaling, (c) whether B-DIM has any direct effect on Wnt signaling in regulating cell proliferation and apoptosis, (d) whether B-DIM has any direct effect on 2-catenin mediated signal transduction and AR trans-activation, (e) whether B-DIM mediated inhibition of PCa cell growth and induction of apoptosis in vitro and in vivo could in part be due to the regulation of 2-catenin mediated signal transduction, and finally (f) does exposure of PCa patients to B-DIM will show B-DIM accumulation in the prostate tumor, which may result in the down-regulation of AR and NF- :B, and nuclear exclusion of 2-catenin. Understanding of the molecular and cellular mechanism by which Akt activates AR and how B-DIM inactivates AR signaling, will have a significant impact on designing non-toxic strategies for the prevention of tumor progression and/or treatment of PCa patients. Thus our proposal is innovative and highly relevant to public health in general and for PCa patients in particular.
This competing renewal application is focused on elucidating the mechanism by which Akt/Wnt activates AR, and assessing how a chemo-preventive agent (B-DIM) could inactivate AR signaling resulting in the inhibition of prostate cancer (PCa) cell growth, invasion and angiogenesis, and causing anti-tumor activity in an animal model. Moreover, based on our phase I clinical trial, we will also conduct a phase II clinical study for assessing whether B-DIM could reach prostate gland and elicit biological effects in PCa patients receiving oral B-DIM. The results of our study will help to design mechanism-based clinical trials for assessing the role of B-DIM in the prevention and/or treatment of PCa.
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