Carcinogenesis Advance Access originally published online on April 19, 2006
Carcinogenesis 2006 27(9):1883-1893; doi:10.1093/carcin/bgl041
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1
, 25-dihydroxyvitamin D3 suppresses interleukin-8-mediated prostate cancer cell angiogenesis
1 Department of Urology, University of Rochester Rochester, NY 14642, USA
2 Department of Chemical Engineering, University of Rochester Rochester, NY 14642, USA
3 Department of Pathology, University of Rochester Rochester, NY 14642, USA
*To whom correspondence and requests for reprints should be addressed: Department of Urology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 656, Rochester, NY 14642, USA. Tel: +1 585 275 9702; Fax: +1 585 756 4133; Email: yifen_lee{at}urmc.rochester.edu
Angiogenesis is an essential step in initial tumor development and metastasis. Consequently, compounds that inhibit angiogenesis would be useful in treating cancer. A variety of antitumor effects mediated by 1
, 25-dihydroxyvitamin D3 (1,25-VD) have been reported, one of which is anti-angiogenesis; however, detailed mechanisms remain unclear. We have demonstrated that 1,25-VD inhibits prostate cancer (PCa) cell-induced human umbilical vein endothelial cell migration and tube formation, two critical steps involved in the angiogenesis. An angiogenesis factor, interleukin-8 (IL-8), secreted from PCa cell was suppressed by 1,25-VD at both mRNA and protein levels. Mechanistic dissection found that 1,25-VD inhibits NF-
B signal, one of the most important IL-8 upstream regulators. The 1,25-VD-mediated NF-B signal reduction was shown to result from the blocking of nuclear translocation of p65, a subunit of the NF-B complex, and was followed by attenuation of the NF-B complex binding to DNA. The role of IL-8 in PCa progression was further examined by PCa tissue microarray analyses. We found that IL-8 expression was elevated during PCa progression, which suggests that IL-8 may play a role in tumor progression mediated through its stimulation on angiogenesis. These findings indicate that 1,25-VD could prevent PCa progression by interrupting IL-8 signaling, which is required in tumor angiogenesis, and thus applying vitamin D in PCa treatment may be beneficial for controlling disease progression.
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