Abstract |
Prostaglandin (PG) E(2) ( PGE(2)) plays a predominant role in promoting colorectal carcinogenesis. The biosynthesis of PGE(2) is accomplished by conversion of the cyclooxygenase (COX) product PGH(2) 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-Delta(12,14)-PGJ(2) and PGA(2) 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 gamma or PGD(2) 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 PGE(2). Our data suggest that there is a feedback mechanism between PGE(2) and CyPGs that implicates mPGES-2 as a new potential target for pharmacological intervention in CRC.
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Authors | Oliver Schröder, Yulyana Yudina, Alan Sabirsh, Nadine Zahn, Jesper Z Haeggström, Jürgen Stein |
Journal | Journal of lipid research
(J Lipid Res)
Vol. 47
Issue 5
Pg. 1071-80
(May 2006)
ISSN: 0022-2275 [Print] United States |
PMID | 16495511
(Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- 15-deoxy-delta(12,14)-prostaglandin J2
- PPAR gamma
- Prostaglandins A
- Receptors, Immunologic
- Receptors, Prostaglandin
- Intramolecular Oxidoreductases
- PTGES protein, human
- PTGES2 protein, human
- Prostaglandin-E Synthases
- prostaglandin A2
- Dinoprostone
- Prostaglandin D2
- prostaglandin D2 receptor
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Topics |
- Caco-2 Cells
- Colonic Neoplasms
(enzymology)
- Dinoprostone
(pharmacology)
- Down-Regulation
- HCT116 Cells
- Humans
- Intramolecular Oxidoreductases
(antagonists & inhibitors)
- Microsomes
(enzymology)
- PPAR gamma
(metabolism)
- Prostaglandin D2
(analogs & derivatives, pharmacology, physiology)
- Prostaglandin-E Synthases
- Prostaglandins A
(pharmacology)
- Receptors, Immunologic
(metabolism)
- Receptors, Prostaglandin
(metabolism)
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