title: Microsomal prostaglandin E synthase-1 is involved in multiple steps of colon carcinogenesis.
abstract: Accumulating evidence indicates that cyclooxygenase (COX)-2-derived prostaglandin (PG) E(2) is involved in the development of various tumors, including colorectal cancer. However, the precise contribution of microsomal PGE synthase (mPGES)-1, a terminal enzyme that acts downstream of COX-2 in the PGE(2)-biosynthetic pathway, to multiple processes of tumor development is not yet fully understood. Here, we show the pro-tumorigenic role of mPGES-1 in chemical carcinogen-induced colon carcinogenesis and intrasplenic tumor transplantation models. Genetic deletion of mPGES-1 significantly reduced both the total number and size of colorectal polyps at 18 weeks after azoxymethane administration with reduced nuclear translocation of β-catenin, altered expression profiles of chemokines/cytokines and increased production of antitumorigenic PGs, prostaglandin D(2) and prostacyclin in tumor tissues. At an early stage (6 weeks), mPGES-1 deficiency significantly reduced the number of aberrant crypt foci, while its transgenic overexpression increased the number. Furthermore, the growth of intrasplenically transplanted tumor cells was suppressed in mPGES-1 knockout (KO) mice. Co-culture of tumor cells with bone marrow-derived macrophages (BM-MΦs) isolated from wild-type (WT) mice resulted in the induction of mPGES-1 in BM-MΦs and increased the growth of tumor cells in vitro, whereas mPGES-1-null BM-MΦs failed to facilitate tumor growth. The adoptive transfer of WT BM-MΦs into mPGES-1 KO mice restored the growth of transplanted tumor cells, indicating that mPGES-1 in MΦs is important for the growth of adjacent tumor cells. Taken together, our findings suggest that the inhibition of mPGES-1 is an alternative therapeutic target for colorectal and possibly other cancers.
authors: Department of Health Chemistry, School of Pharmacy, Showa University, Tokyo, Japan.
authors: Y
authors: Y
authors: Sasaki
authors: D
authors: D
authors: Kamei
authors: Y
authors: Y
authors: Ishikawa
authors: T
authors: T
authors: Ishii
authors: S
authors: S
authors: Uematsu
authors: S
authors: S
authors: Akira
authors: M
authors: M
authors: Murakami
authors: S
authors: S
authors: Hara
mesh_terms: D058739:Aberrant Crypt Foci / Q000139:chemically induced / Q000201:enzymology; D000230:Adenocarcinoma / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D000818:Animals; D001397:Azoxymethane / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000473:pathology*; D018920:Coculture Techniques; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D003111:Colonic Polyps / Q000139:chemically induced / Q000201:enzymology; D016207:Cytokines / Q000096:biosynthesis; D020869:Gene Expression Profiling; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008861:Microsomes / Q000201:enzymology*; D009368:Neoplasm Transplantation; D000071876:Prostaglandin-E Synthases; D011453:Prostaglandins / Q000096:biosynthesis; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495267:CTNNB1 protein, mouse; D002273:Carcinogens; D016207:Cytokines; D011453:Prostaglandins; D051176:beta Catenin; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D001397:Azoxymethane