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CCAAT/Enhancer-Binding Protein : A Molecular Target of 1,25-Dihydroxyvitamin D₃ in Androgen-Responsive Prostate Cancer LNCaP Cells

¹ Division of Hematology/Oncology, Cedars-Sinai Medical Center, University of California at Los Angeles School of Medicine, Los Angeles, California; ² Department of Internal Medicine, Kochi Medical School, Kochi, Japan; and ³ Leo Pharmaceuticals, Ballerup, Denmark

Requests for reprints: Takayuki Ikezoe, Department of Internal Medicine, Kochi Medical School, Nankoku, Kochi 783-8505, Japan. Phone: 81-88-880-2345; Fax: 81-88-880-2348; E-mail: ikezoet{at}med.kochi-ms.ac.jp.

1,25-Dihydroxyvitamin D₃ [1,25(OH)₂D₃], the active metabolite of vitamin D₃, inhibits the proliferation of prostate cancer cells. However, the molecular mechanisms by which 1,25(OH)₂D₃ inhibits the proliferation of these cells remain to be fully elucidated. In this study, we used microarray technology to identify target genes of 1,25(OH)₂D₃ in androgen-responsive prostate cancer LNCaP cells. 1,25(OH)₂D₃ up-regulated CCAAT/enhancer-binding protein (C/EBP) by 5-fold in these cells. Knockdown of C/EBP expression by RNA interference showed that C/EBP is essential for the significant growth inhibition of LNCaP cells in response to 1,25(OH)₂D₃ treatment. Moreover, we found that 1,25(OH)₂D₃ induced C/EBP in other cancer cells, including the estrogen receptor (ER)–expressing MCF-7 and T47D breast cancer cells that are sensitive to the growth inhibitory effects of 1,25(OH)₂D₃. On the other hand, 1,25(OH)₂D₃ was not able to induce C/EBP in either androgen receptor–negative PC-3 and DU145 or ER-negative breast cancer MDA-MB-231 cells that were relatively resistant to growth inhibition by 1,25(OH)₂D₃. Furthermore, forced expression of C/EBP in prostate cancer LNCaP as well as breast cancer MCF-7 and T47D cells dramatically reduced their clonal growth. Taken together, forced expression of C/EBP in cancer cells may be a promising therapeutic strategy.

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