Genetic deletion of mPGES-1 accelerates intestinal tumorigenesis in APC(Min/+) mice.
The induced synthesis of bioactive prostanoids downstream of cyclooxygenase-2 (COX-2) and prostaglandin H(2) (PGH(2)) exerts a critical event in colorectal carcinogenesis. Here we demonstrate that APC(Min/+) mice with genetic deletion of microsomal prostaglandin E synthase-1 (mPGES-1), which catalyses the terminal conversion of PGH(2) into PGE(2), surprisingly develop more and generally larger intestinal tumors than do mPGES-1 wild type littermates (mean number of tumors/intestine 80 vs. 38, p<0.0005, mean tumor diameter 1.64 vs. 1.12 mm, p<0.0005). No deviation regarding the expression of other PGE(2) related enzymes (COX-1, COX-2, mPGES-2, cPGES, and 15-PGDH) or receptors (EP1-4) was obvious among the mPGES-1 deficient mice. PGE(2) levels were suppressed in tumors of mPGES-1 deficient animals, but the concentrations of other PGH(2) derived prostanoids were generally enhanced, being most prominent for TxA(2) and PGD(2). Thus, we hypothesise that a redirected synthesis towards other lipid mediators might (over)compensate for loss of mPGES-1/PGE(2) during intestinal tumorigenesis. Nevertheless, our results question the suitability for mPGES-1 targeting therapy in the treatment or prevention of colorectal cancer.
Elander
N
N
Department of Clinical and Experimental Medicine, Division of Cell Biology, Faculty of Health Sciences, Linköping University, SE-58185 Linköping, Sweden. nilel@ibk.liu.se
Ungerbäck
J
J
Olsson
H
H
Uematsu
S
S
Akira
S
S
Söderkvist
P
P
D015121:6-Ketoprostaglandin F1 alpha / Q000032:analysis; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D015232:Dinoprostone / Q000032:analysis / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D019746:Intramolecular Oxidoreductases / Q000235:genetics*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D000071876:Prostaglandin-E Synthases; D012333:RNA, Messenger / Q000378:metabolism; D013929:Thromboxane B2 / Q000032:analysis
D012333:RNA, Messenger; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; C000605866:Ptges2 protein, mouse; D015232:Dinoprostone