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J. Biol. Chem., Vol. 283, Issue 26, 18441-18449, June 27, 2008

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In Vivo and in Vitro Regulation of Syndecan 1 in Prostate Cells by n-3 Polyunsaturated Fatty Acids^*

Iris J. Edwards¹, Haiguo Sun, Yunping Hu, Isabelle M. Berquin, Joseph T. O'Flaherty, J. Mark Cline, Lawrence L. Rudel, and Yong Q. Chen^¶

From the Departments of Pathology, Medicine, and ^¶Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157

Syndecan 1 is the major proteoglycan produced by epithelial cells. It is strategically localized at the plasma membrane to participate in growth factor signaling and cell-cell and cell-matrix interactions. Its expression may modulate the properties of epithelial lineage tumor cells in which it is generally down-regulated compared with nontumor progenitors. The present study examined the regulation of syndecan 1 in prostate epithelial cells by n-3 polyunsaturated fatty acids. In prostate tissue of mice, syndecan 1 immunostaining was demonstrated in epithelial cells throughout each gland. In animals fed an n-3 polyunsaturated fatty acid-enriched diet, syndecan 1 mRNA was increased in all prostate glands. In the human prostate cancer cell line, PC-3, delivery of exogenous n-3 (but not n-6) fatty acids resulted in up-regulation of syndecan 1 expression. This effect was mimicked by a peroxisome proliferator-activated receptor (PPAR) agonist, troglitazone, and inhibited in the presence of a PPAR antagonist and in cells transfected with dominant negative PPAR cDNA. Using a luciferase gene driven either by a PPAR response element or by a DR-1 site present in the syndecan 1 promoter, reporter activation was increased by n-3 low density lipoprotein, docosahexaenoic acid, and troglitazone, whereas activity of a luciferase gene placed downstream of a mutant DR-1 site was unresponsive. These findings indicate that syndecan 1 is up-regulated by n-3 fatty acids by a transcriptional pathway involving PPAR. This mechanism may contribute to the chemopreventive properties of n-3 fatty acids in prostate cancer.

Received for publication, March 17, 2008

^* This work was supported, in whole or in part, by National Institutes of Health Grants P01CA106742 (to Y. Q. C., I. J. E., J. T. O., and J. M. C.), R01CA115958 (to I. J. E.), RO1CA114017 (to I. M. B.), HL-49373 (to L. L. R.), and R01CA107668 (to Y. Q. C.). 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.

¹ To whom correspondence should be addressed: Dept. of Pathology-Tumor Biology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157. Tel.: 336-716-2677; Fax: 336-716-6757; E-mail: iedwards{at}wfubmc.edu.

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