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 b-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-MUs) isolated from wild-type (WT) mice resulted in the induction of mPGES-1 in BM-MUs and increased the growth of tumor cells in vitro, whereas mPGES-1-null BM-MUs failed to facilitate tumor growth. The adoptive transfer of WT BM-MUs into mPGES-1 KO mice restored the growth of transplanted tumor cells, indicating that mPGES-1 in MUs 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.

The role of heat shock proteins in inflammatory injury induced by cold stress in chicken hearts

“…COX-2 inhibitors reduce mucosal damage, which further indicates the role of prostaglandins in tissue damage and inflammation reactions (Zheng et al 2012). PTGES catalyzes the isomerization of PGH2 to PGE2, and the latter plays an important role in inflammation (Liu et al 2012a), cell growth, and transformation (Sasaki et al 2012). In the current study, we found that the NF-κB, iNOS, and TNF-α mRNA levels of heart tissue were significantly increased (P < 0.05) in stress groups.…”

The Molecular Basis for the Pharmacokinetics and Pharmacodynamics of Curcumin and Its Metabolites in Relation to Cancer

“…In doing so, curcumin deters the conversion of COX-2-derived PGH 2 to PGE 2 (Fig. 19) (Jakobsson et al, 1999;Samuelsson et al, 2007), a reaction that recently was deemed critical in the onset and progression of colorectal cancer (Sasaki et al, 2012). Because of these PG-inhibitory effects, curcumin has been shown to promote cancer cell apoptosis, decelerate angiogenesis, and facilitate the clearance of malignant lesions by the immune system.…”

Regulation of 15-hydroxyprostaglandin dehydrogenase expression in hepatocellular carcinoma

“…Regarding mPGES-1, it participates in various pathophysiological states in which COX-2 is involved. Consistent with the role of mPGES-1 for PGE 2 synthesis, mPGES-1 knockdown has been shown to reduce PGE 2 levels and reduce tumor proliferation and/or invasiveness in several tumor cell types through a EGR1/β-catenin signaling axis (Donnini, Finetti, 2011, Sasaki, Kamei, 2011. The third enzyme involved in PGE 2 homeostasis, 15-PGDH, also plays an important role in carcinogenesis.…”

“…Recently, more evidence has suggested that mPGES-1 participates in various pathophysiological states in which COX-2 is involved. Consistent with the role of mPGES-1 for PGE 2 synthesis, mPGES-1 knockdown has been shown to inhibit PGE 2 production and reduce tumor proliferation and/or invasiveness of several tumor cell types including Lewis lung carcinoma cells, human prostate cancer cell lines and colorectal cancer cells, through a novel EGR1/β-catenin signaling axis (Sasaki et al , 2011).…”