title: Genetic deletion of mPGES-1 suppresses intestinal tumorigenesis.
abstract: Elevated levels of prostaglandin E(2) (PGE(2)) are often found in colorectal cancers. Thus, nonsteroidal anti-inflammatory drugs, including selective cyclooxygenase-2 (COX-2) inhibitors, are among the most promising chemopreventive agents for colorectal cancer. However, their long-term use is restricted by the occurrence of adverse events believed to be associated with a global reduction in prostaglandin production. In the present study, we evaluated the chemopreventive efficacy of targeting the terminal synthase microsomal PGE(2) synthase 1 (mPGES-1), which is responsible for generating PGE(2), in two murine models of intestinal cancer. We report for the first time that genetic deletion of mPGES-1 in Apc-mutant mice results in marked and persistent suppression of intestinal cancer growth by 66%, whereas suppression of large adenomas (>3 mm) was almost 95%. This effect occurred despite loss of Apc heterozygosity and beta-catenin activation. However, we found that mPGES-1 deficiency was associated with a disorganized vascular pattern within primary adenomas as determined by CD31 immunostaining. We also examined the effect of mPGES-1 deletion on carcinogen-induced colon cancer. The absence of mPGES-1 reduced the size and number of preneoplastic aberrant crypt foci (ACF). Importantly, mPGES-1 deletion also blocked the nuclear accumulation of beta-catenin in ACF, confirming that beta-catenin is a critical target of PGE(2) procarcinogenic signaling in the colon. Our data show the feasibility of targeting mPGES-1 for cancer chemoprevention with the potential for improved tolerability over traditional nonsteroidal anti-inflammatory drugs and selective COX-2 inhibitors.
authors.affiliation: Center for Molecular Medicine, Department of Cell Biology, University of Connecticut Health Center, Farmington, CT 06030-3101, USA.
authors.forename: Masako
authors.initials: M
authors.lastname: Nakanishi
authors.forename: David C
authors.initials: DC
authors.lastname: Montrose
authors.forename: Patsy
authors.initials: P
authors.lastname: Clark
authors.forename: Prashant R
authors.initials: PR
authors.lastname: Nambiar
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Belinsky
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Claffey
authors.forename: Daigen
authors.initials: D
authors.lastname: Xu
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Rosenberg
mesh_terms: D000236:Adenoma / Q000235:genetics*; D000818:Animals; D049109:Cell Proliferation; D015232:Dinoprostone / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D017353:Gene Deletion; D006720:Homozygote; D007414:Intestinal Neoplasms / Q000098:blood supply / Q000235:genetics*; D007417:Intestinal Polyps / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007421:Intestine, Small / Q000098:blood supply / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000235:genetics* / Q000502:physiology; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000071876:Prostaglandin-E Synthases; D021381:Protein Transport; D051176:beta Catenin / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D051176:beta Catenin; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone