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Seok Joo Kwon
Thesis Advisor: Isaac Yi Kim, MD, PhD
Graduate Program: Cell and Developmental Biology
Medical Education Building
Conference Room, Room 102
Friday, July 31, 2009
Prostate cancer is the most commonly diagnosed cancer in men in the US. Active surveillance, radiation, and surgery are the recommended treatments for localized prostate cancer. However, approximately 35% of patients eventually develop biochemical recurrence within 5 years after the initial treatment. In the present study, we have investigated the tumorigenic potential of bone morphogenetic protein-6 (BMP-6) in prostate cancer cells. BMP-6 enhanced tumor growth in mice but not in tissue culture. BMP-6 activated macrophages and dramatically increased the production of interleukin-1alpha (IL-1alpha) in vitro. Mechanistically, optimal ligand/receptor/Smad combination for IL-1alpha induction was BMPRII (BMP type II receptor), ALK3 (BMP type I receptor), and Smad 1(R-Smad)/4(Co-Smad). We used a serial promoter deletion assay and found that -1,856~-1,655 bp region of IL-1alpha promoter contained the BMP-6 responsive element. Surprisingly, this region did not have the consensus Smad binding element. Additional analysis of this 200 bp region demonstrated multiple NF-kappaB binding sites. When NF-kappaB was inhibited, IL-1alpha induction was completely blocked. Moreover, BMP-6 increased NF-kappaB reporter vector activity and phosphorylated p50 and p65, suggesting that NF-kappaB’s role in induction of IL-1alpha by BMP-6. Immunoprecipitation (IP) and chromatin immunoprecipitation (ChIP) showed that Smad1 is bound to 200 bp region and interact with NF-kappaB directly. Finally, VEGF expression increased in TRAMP-C2 prostate cancer cells co-cultured with macrophages and tube formation of endothelial cell was increased. Based on these results, we propose that tumor-derived BMP-6 induces IL-1alpha expression in macrophages and that this induction requires Smad and NF-kappaB pathways; IL-1alpha, in turn, induces angiogenesis in prostate cancer.