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Effect of Bone Morphogenetic Protein-6 on Tumorigenic Potential of Prostate Cancer Cells

by
Seok Joo Kwon
MS, 2001
Korea University
Seoul, Korea

Thesis Advisor: Isaac Yi Kim, MD, PhD

Graduate Program: Cell and Developmental Biology

Medical Education Building
Conference Room, Room 102
New Brunswick

Friday, July 31, 2009
9:30 am


Abstract

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-kappaBs 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.


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