Abstract
<div>Abstract<p>Vitamin D has broad range of physiological functions and antitumor effects. 24-Hydroxylase, encoded by the <i>CYP24A1</i> gene, is the key enzyme for degrading many forms of vitamin D including the most active form, 1,25D<sub>3</sub>. Inhibition of <i>CYP24A1</i> enhances 1,25D<sub>3</sub> antitumor activity. To isolate regulators of <i>CYP24A1</i> expression in prostate cancer cells, we established a stable prostate cancer cell line PC3 with <i>CYP24A1</i> promoter driving luciferase expression to screen a small molecular library for compounds that inhibit <i>CYP24A1</i> promoter activity. From this screening, we identified, 4,5,6,7-tetrabromobenzimidazole (TBBz), a protein kinase CK2 selective inhibitor as a disruptor of <i>CYP24A1</i> promoter activity. We show that TBBz inhibits <i>CYP24A1</i> promoter activity induced by 1,25D<sub>3</sub> in prostate cancer cells. In addition, TBBz downregulates endogenous <i>CYP24A1</i> mRNA level in TBBz-treated PC3 cells. Furthermore, siRNA-mediated CK2 knockdown reduces 1,25D<sub>3</sub>-induced <i>CYP24A1</i> mRNA expression in PC3 cells. These results suggest that CK2 contributes to 1,25D<sub>3</sub>-mediated target gene expression. Finally, inhibition of CK2 by TBBz or CK2 siRNA significantly enhances 1,25D<sub>3</sub>-mediated antiproliferative effect <i>in vitro</i> and <i>in vivo</i> in a xenograft model. In summary, our findings reveal that protein kinase CK2 is involved in the regulation of <i>CYP24A1</i> expression by 1,25D<sub>3</sub> and CK2 inhibitor enhances 1,25D<sub>3</sub>-mediated antitumor effect. <i>Cancer Res; 73(7); 2289–97. ©2013 AACR</i>.</p></div>
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