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J. Biol. Chem., Vol. 280, Issue 1, 476-483, January 7, 2005

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Prostaglandin E₂ Regulates the Complement Inhibitor CD55/Decay-accelerating Factor in Colorectal Cancer^*

Vijaykumar R. Holla, Dingzhi Wang, Joanne R. Brown, Jason R. Mann, Sharada Katkuri, and Raymond N. DuBois¶

From the Department of Medicine, Vanderbilt University Medical Center and the Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee 37232-2279

Cyclooxygenase-derived prostaglandin E₂ (PGE₂) stimulates tumor progression by modulating several proneoplastic pathways. The mechanisms by which PGE₂ promotes tumor growth and metastasis through stimulation of cell migration, invasion, and angiogenesis have been fairly well characterized. Much less is known, however, about the molecular mechanisms responsible for the immunosuppressive effects of PGE₂. We identified PGE₂ target genes and subsequently studied their biologic role in colorectal cancer cells. The complement regulatory protein decay-accelerating factor (DAF or CD55) was induced following PGE₂ treatment of LS174T colon cancer cells. Analysis of PGE₂-mediated activation of the DAF promoter employing 5'-deletion luciferase constructs suggests that regulation occurs at the transcriptional level via a cyclic AMP/protein kinase A-dependent pathway. Nonsteroidal anti-inflammatory drugs blocked DAF expression in HCA-7 colon cancer cells, which could be restored by the addition of exogenous PGE₂. Finally, we observed an increase in DAF expression in the intestinal mucosa of Apc^Min+/- mice treated with PGE₂ in vivo. In summary, these results indicate a novel immunosuppressive role for PGE₂ in the development of colorectal carcinomas.

Received for publication, July 2, 2004 , and in revised form, September 14, 2004.

^* This work was supported in part by United States Public Health Services Grants RO-DK-62112 and P0-CA-77839. 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.

^¶ Hortense B. Ingram Professor of Molecular Oncology and the recipient of a National Institutes of Health MERIT award (R37-DK47297). To whom correspondence should be addressed: Vanderbilt-Ingram Cancer Center, 691 Preston Bldg., 2300 Pierce Ave., Nashville, TN 37232-6838. Tel.: 615-343-0527; Fax: 615-936-6865; E-mail: raymond.dubois{at}vanderbilt.edu.

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