Role of the prostaglandin E receptor subtype EP1 in colon carcinogenesis

Although the cyclooxygenase pathway of the arachidonic acid cascade has bee n suggested to play an important role in colon carcinogenesis, the molecula r species of prostanoids and receptors involved have not been fully elucida ted yet. We examined the development of aberrant crypt foci (ACFs), putativ e preneoplastic lesions of the colon, in two lines of knockout mice, each d eficient in prostaglandin E receptors, EP1 and EP3, by treatment with the c olon carcinogen, azoxymethane. Formation of ACFs was decreased only in the FP1-knockout mice to similar to 60% of the Level in wild-type mice. Adminis tration of 250, 500, or 1000 ppm of a novel selective EP1 antagonist, ONO-8 711, in the diet to azoxymethane-treated C57BL/6J mice also resulted in a d ose-dependent reduction of ACF formation. Moreover, when Min mice, having a nonsense mutation in the adenomatous polyposis coil gene, were given 500 p pm ONO-8711 in the diet, the number of intestinal polyps was significantly reduced to 57% of that in the basal diet group. These results strongly sugg est that prostaglandin E-2 contributes to colon carcinogenesis to some exte nt through its action at the EP1 receptor. Thus, EP1 antagonists may be goo d candidates as chemopreventive agents for colon cancer.