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Journal of Lipid Research, Vol. 47, 1071-1080, May 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

15-deoxy-^12,14-prostaglandin J₂ inhibits the expression of microsomal prostaglandin E synthase type 2 in colon cancer cells

Oliver Schröder^1,*, Yulyana Yudina^*, Alan Sabirsh, Nadine Zahn^*, Jesper Z. Haeggström^2, and Jürgen Stein^2,*

^* First Department of Medicine, Division of Gastroenterology, Center for Drug Research, Development and Saftey (ZAFES), Johann Wolfgang Goethe University, 60590 Frankfurt/Main, Germany
Department of Medical Biochemistry and Biophysics, Division of Chemistry II, Karolinska Institutet, 17177 Stockholm, Sweden

Published, JLR Papers in Press, March 2, 2006.

² J. Z. Haeggström and J. Stein contributed equally to this work.

¹ To whom correspondence should be addressed. e-mail: o.schroeder{at}em.uni-frankfurt.de

Prostaglandin (PG) E₂ (PGE₂) plays a predominant role in promoting colorectal carcinogenesis. The biosynthesis of PGE₂ is accomplished by conversion of the cyclooxygenase (COX) product PGH₂ by several terminal prostaglandin E synthases (PGES). Among the known PGES isoforms, microsomal PGES type 1 (mPGES-1) and type 2 (mPGES-2) were found to be overexpressed in colorectal cancer (CRC); however, the role and regulation of these enzymes in this malignancy are not yet fully understood. Here, we report that the cyclopentenone prostaglandins (CyPGs) 15-deoxy-^12,14-PGJ₂ and PGA₂ downregulate mPGES-2 expression in the colorectal carcinoma cell lines Caco-2 and HCT 116 without affecting the expression of any other PGES or COX. Inhibition of mPGES-2 was subsequently followed by decreased microsomal PGES activity. These effects were mediated via modulation of the cellular thiol-disulfide redox status but did not involve activation of the peroxisome proliferator-activated receptor or PGD₂ receptors. CyPGs had antiproliferative properties in vitro; however, this biological activity could not be directly attributed to decreased PGES activity because it could not be reversed by adding PGE₂. Our data suggest that there is a feedback mechanism between PGE₂ and CyPGs that implicates mPGES-2 as a new potential target for pharmacological intervention in CRC.

Abbreviations: AA, arachidonic acid; COX, cyclooxygenase; cPGES, cytosolic prostaglandin E synthase; CRC, colorectal cancer; CyPG, cyclopentenone prostaglandin; DP, prostaglandin D₂ receptor; 15d-PGJ₂, 15-deoxy-^12,14-prostaglandin J₂; EP, prostaglandin E₂ receptor; mPGES, microsomal prostaglandin E synthase; NSAID, nonsteroidal antiinflammatory drug; PGES, prostaglandin E synthase; PPAR, peroxisome proliferator-activated receptor

Supplementary key words colorectal cancer • cyclopentenone prostaglandins • feedback control • proliferation • prostaglandin E₂ • redox status

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