Microsomal prostaglandin E synthase-1 is involved in multiple steps of colon carcinogenesis

Y Sasaki, D Kamei, Y Ishikawa, T Ishii, S Uematsu… - Oncogene, 2012 - nature.com
Y Sasaki, D Kamei, Y Ishikawa, T Ishii, S Uematsu, S Akira, M Murakami, S Hara
Oncogene, 2012nature.com
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 …
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.
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