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J. Biol. Chem., Vol. 280, Issue 42, 35458-35468, October 21, 2005

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Suppression of Death Receptor-mediated Apoptosis by 1,25-Dihydroxyvitamin D3 Revealed by Microarray Analysis^*

From the Departments of Pathology and Interdisciplinary Oncology, University of South Florida College of Medicine and Programs of Molecular Oncology and Drug Discovery, H. Lee Moffitt Cancer Center, Tampa, Florida 33612

Recent studies suggest that growth inhibition by 1,25-dihydroxyvitamin D₃ represents an innovative approach to ovarian cancer therapy. To understand the molecular mechanism of 1,25-dihydroxyvitamin D₃ action, we profiled the hormone-induced changes in the transcriptome of ovarian cancer cells using microarray technology. More than 200 genes were identified to be regulated by 1,25-dihydroxyvitamin D₃. Reverse transcription-PCR analyses confirmed the regulation of a group of apoptosis-related genes, including the up-regulation of the decoy receptor that inhibits tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) action, TRAIL receptor 4, and the down-regulation of Fas, the receptor that mediates the action of Fas ligand. The regulation was further confirmed at the protein level. Consistent with the regulation of the death receptors, pretreatment with 1,25-dihydroxyvitamin D₃ decreased apoptosis induced by TRAIL and Fas ligand. Because persistent 1,25-dihydroxyvitamin D₃ treatment has been shown to induce apoptosis in ovarian cancer, the hormone appears to exert a dual effect on the death of ovarian cancer cells. Knockdown of TRAIL receptor 4 by RNA interference or ectopic expression of Fas relieved the suppressive effect of 1,25-dihydroxyvitamin D₃, showing that molecular manipulation of death receptors is a viable approach to overcome the protective effect of 1,25-dihydroxyvitamin D₃ on the apoptosis of ovarian cancer. These strategies may allow ovarian cancer patients to benefit from therapy with both 1,25-dihydroxyvitamin D₃ and ligands for death receptors, such as TRAIL, shown to selectively induce apoptosis in cancer but not normal cells.

Received for publication, June 20, 2005 , and in revised form, July 27, 2005.

^* This work was supported by New Investigator Award DAMD17-01-1-0731 from U. S. Department of Defense Ovarian Cancer Program and NCI, National Institutes of Health Grant 1R01 CA111334 (to W. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1 and S2.

¹ To whom correspondence should be addressed: Dept. of Pathology, University of South Florida College of Medicine, 12901 Bruce B. Downs Blvd., MDC 11, Tampa, FL 33612-4799. Tel.: 813-974-0561; Fax: 813-974-5536; E-mail: wbai{at}hsc.usf.edu.

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