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.