title: Selective PGE(2) suppression inhibits colon carcinogenesis and modifies local mucosal immunity.
abstract: Prostaglandin E(2) (PGE(2)) is a bioactive lipid that mediates a wide range of physiologic effects and plays a central role in inflammation and cancer. PGE(2) is generated from arachidonic acid by the sequential actions of the COX and terminal synthases (PGES). Increased levels of COX-2, with a concomitant elevation of PGE(2), are often found in colorectal cancers (CRC), providing the rationale for the use of COX-2 inhibitors for chemoprevention. Despite their proven efficacy in cancer prevention, however, COX-2 inhibitors exhibit dose-dependent toxicities that are mediated in part by their nonspecific reduction of essential prostanoids, thus limiting their chemopreventive benefit. To achieve enhanced specificity, recent efforts have been directed toward targeting the inducible terminal synthase in the production of PGE(2), microsomal PGES (mPGES-1). In the present study, we show that genetic deletion of mPGES-1 affords significant protection against carcinogen-induced colon cancer. mPGES-1 gene deletion results in an about 80% decrease in tumor multiplicity and up to a 90% reduction in tumor load in the distal colon of azoxymethane (AOM)-treated mice. Associated with the striking cancer suppression, we have identified a critical role for PGE(2) in the control of immunoregulatory cell expansion (FoxP3-positive regulatory T cells) within the colon-draining mesenteric lymph nodes, providing a potential mechanism by which suppression of PGE(2) may protect against CRC. These results provide new insights into how PGE(2) controls antitumor immunity.
authors.affiliation: Center for Molecular Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA.
authors.forename: Masako
authors.initials: M
authors.lastname: Nakanishi
authors.forename: Antoine
authors.initials: A
authors.lastname: Menoret
authors.forename: Takuji
authors.initials: T
authors.lastname: Tanaka
authors.forename: Shingo
authors.initials: S
authors.lastname: Miyamoto
authors.forename: David C
authors.initials: DC
authors.lastname: Montrose
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Vella
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Rosenberg
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D016718:Arachidonic Acid / Q000378:metabolism; D001397:Azoxymethane / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D017353:Gene Deletion; D018928:Immunity, Mucosal; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D008198:Lymph Nodes / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008861:Microsomes / Q000378:metabolism; D000071876:Prostaglandin-E Synthases
chemical_list: D016588:Anticarcinogenic Agents; D016718:Arachidonic Acid; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone; D001397:Azoxymethane