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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA083695-09
Application #
8078123
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Perloff, Marjorie
Project Start
1999-12-01
Project End
2013-05-31
Budget Start
2011-06-01
Budget End
2013-05-31
Support Year
9
Fiscal Year
2011
Total Cost
$260,244
Indirect Cost
Name
Wayne State University
Department
Pathology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Kong, Dejuan; Sethi, Seema; Li, Yiwei et al. (2015) Androgen receptor splice variants contribute to prostate cancer aggressiveness through induction of EMT and expression of stem cell marker genes. Prostate 75:161-74
Ahmad, Aamir; Li, Yiwei; Bao, Bin et al. (2014) Epigenetic regulation of miRNA-cancer stem cells nexus by nutraceuticals. Mol Nutr Food Res 58:79-86
Li, Yiwei; Ahmad, Aamir; Kong, Dejuan et al. (2014) Recent progress on nutraceutical research in prostate cancer. Cancer Metastasis Rev 33:629-40
Sethi, Sajiv; Li, Yiwei; Sarkar, Fazlul H (2013) Regulating miRNA by natural agents as a new strategy for cancer treatment. Curr Drug Targets 14:1167-74
Ahmad, Aamir; Biersack, Bernhard; Li, Yiwei et al. (2013) Perspectives on the role of isoflavones in prostate cancer. AAPS J 15:991-1000
Li, Yiwei; Kong, Dejuan; Ahmad, Aamir et al. (2013) Pancreatic cancer stem cells: emerging target for designing novel therapy. Cancer Lett 338:94-100
Li, Yiwei; Kong, Dejuan; Ahmad, Aamir et al. (2013) Antioxidant function of isoflavone and 3,3'-diindolylmethane: are they important for cancer prevention and therapy? Antioxid Redox Signal 19:139-50
Kong, Dejuan; Heath, Elisabeth; Chen, Wei et al. (2012) Loss of let-7 up-regulates EZH2 in prostate cancer consistent with the acquisition of cancer stem cell signatures that are attenuated by BR-DIM. PLoS One 7:e33729
Kong, Dejuan; Ahmad, Aamir; Bao, Bin et al. (2012) Histone deacetylase inhibitors induce epithelial-to-mesenchymal transition in prostate cancer cells. PLoS One 7:e45045
Kong, Dejuan; Heath, Elisabeth; Chen, Wei et al. (2012) Epigenetic silencing of miR-34a in human prostate cancer cells and tumor tissue specimens can be reversed by BR-DIM treatment. Am J Transl Res 4:14-23

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