15-deoxy-Delta12,14-prostaglandin J2 inhibits the expression of microsomal prostaglandin E synthase type 2 in colon cancer cells.
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.
First Department of Medicine, Division of Gastroenterology, Center for Drug Research, Development and Saftey (ZAFES), Johann Wolfgang Goethe University, Frankfurt/Main, Germany. o.schroender@em.uni-frankfurt.de
Oliver
O
Schröder
Yulyana
Y
Yudina
Alan
A
Sabirsh
Nadine
N
Zahn
Jesper Z
JZ
Haeggström
Jürgen
J
Stein
D018938:Caco-2 Cells; D003110:Colonic Neoplasms / Q000201:enzymology*; D015232:Dinoprostone / Q000494:pharmacology; D015536:Down-Regulation; D045325:HCT116 Cells; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors*; D008861:Microsomes / Q000201:enzymology; D047495:PPAR gamma / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology; D000071876:Prostaglandin-E Synthases; D011454:Prostaglandins A / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000378:metabolism
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D047495:PPAR gamma; D011454:Prostaglandins A; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; C000605863:PTGES2 protein, human; D000071876:Prostaglandin-E Synthases; C100008:prostaglandin A2; D015232:Dinoprostone; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor