title: Involvement of prostaglandin E receptor subtype EP(4) in colon carcinogenesis.
abstract: Accumulating evidence indicates that overproduction of prostanoids attributable to overexpression of cyclooxygenase-2 (COX-2) plays an important role in colon carcinogenesis. We have shown recently that the prostaglandin (PG) E receptor, EP(1), but not EP(3), is involved in mouse colon carcinogenesis. In line with our previous study, here we examined the role of prostanoid receptors in colon carcinogenesis using six additional lines of knockout mice deficient in prostanoid receptors EP(2), EP(4), DP, FP, IP, or TP. The animals were treated with the colon carcinogen, azoxymethane (AOM), and examined for the development of aberrant crypt foci (ACFs), putative preneoplastic lesions in the colon. Formation of ACFs was decreased only in the EP(4)-knockout mice, to 56% of the wild-type level. To confirm these results, we also examined the inhibitory effects of an EP(4)-selective antagonist, ONO-AE2-227, in the diet on the formation of AOM-induced colon ACFs in C57BL/6Cr mice and on the development of intestinal polyps in Min mice. ONO-AE2-227 at a dose of 400 ppm reduced the formation of ACFs to 67% of the control level, and intestinal polyp numbers in Min mice receiving 300 ppm were decreased to 69% of the control level. Plating efficiency assays showed that addition of 1.0 microM ONO-AE1-329, an EP(4)-selective agonist, resulted in a 1.8-fold increase in the colony number of the human colon cancer cell line, HCA-7, similar to the effect of PGE(2). Moreover, EP(4) mRNA expression was clearly observed in normal colon mucosa and colon tumors in mice. Our previous and present results indicate that PGE(2) contributes to colon carcinogenesis through its actions mediated through EP(1) and EP(4) receptors; therefore, antagonists for these two receptors may be good candidates as chemopreventive agents against colon cancer.
authors.affiliation: Cancer Prevention Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Mutoh
authors.forename: Kouji
authors.initials: K
authors.lastname: Watanabe
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kitamura
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Shoji
authors.forename: Mami
authors.initials: M
authors.lastname: Takahashi
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Kawamori
authors.forename: Kousuke
authors.initials: K
authors.lastname: Tani
authors.forename: Michiyoshi
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Maruyama
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Shuichi
authors.initials: S
authors.lastname: Ohuchida
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Sugimoto
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
authors.forename: Takashi
authors.initials: T
authors.lastname: Sugimura
authors.forename: Keiji
authors.initials: K
authors.lastname: Wakabayashi
mesh_terms: D000818:Animals; D001397:Azoxymethane; D002273:Carcinogens; D002455:Cell Division / Q000502:physiology; D003106:Colon / Q000378:metabolism; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology; D005260:Female; D007417:Intestinal Polyps / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011230:Precancerous Conditions / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D058309:Receptors, Prostaglandin E, EP4 Subtype
chemical_list: D002273:Carcinogens; C545650:PTGER4 protein, human; C545651:Ptger4 protein, mouse; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015232:Dinoprostone; D001397:Azoxymethane