Genetic deletion of mPGES-1 suppresses intestinal tumorigenesis.

Abstract

Elevated levels of prostaglandin E(2) (PGE(2)) are often found in colorectal cancers. Thus, nonsteroidal anti-inflammatory drugs, including selective cyclooxygenase-2 (COX-2) inhibitors, are among the most promising chemopreventive agents for colorectal cancer. However, their long-term use is restricted by the occurrence of adverse events believed to be associated with a global reduction in prostaglandin production. In the present study, we evaluated the chemopreventive efficacy of targeting the terminal synthase microsomal PGE(2) synthase 1 (mPGES-1), which is responsible for generating PGE(2), in two murine models of intestinal cancer. We report for the first time that genetic deletion of mPGES-1 in Apc-mutant mice results in marked and persistent suppression of intestinal cancer growth by 66%, whereas suppression of large adenomas (>3 mm) was almost 95%. This effect occurred despite loss of Apc heterozygosity and beta-catenin activation. However, we found that mPGES-1 deficiency was associated with a disorganized vascular pattern within primary adenomas as determined by CD31 immunostaining. We also examined the effect of mPGES-1 deletion on carcinogen-induced colon cancer. The absence of mPGES-1 reduced the size and number of preneoplastic aberrant crypt foci (ACF). Importantly, mPGES-1 deletion also blocked the nuclear accumulation of beta-catenin in ACF, confirming that beta-catenin is a critical target of PGE(2) procarcinogenic signaling in the colon. Our data show the feasibility of targeting mPGES-1 for cancer chemoprevention with the potential for improved tolerability over traditional nonsteroidal anti-inflammatory drugs and selective COX-2 inhibitors.

• Authors: Masako Nakanishi, David C Montrose, Patsy Clark, Prashant R Nambiar, Glenn S Belinsky, Kevin P Claffey, Daigen Xu, Daniel W Rosenberg
• Journal: Cancer research (Cancer Res) Vol. 68 Issue 9 Pg. 3251-9 (May 01 2008) ISSN: 1538-7445 [Electronic] United States
• PMID: 18451151 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Isoenzymes
• beta Catenin
• Intramolecular Oxidoreductases
• Prostaglandin-E Synthases
• Ptges protein, mouse
• Dinoprostone

Topics

• Adenoma (genetics)
• Animals
• Cell Proliferation
• Dinoprostone (metabolism)
• Disease Progression
• Female
• Gene Deletion
• Homozygote
• Intestinal Neoplasms (blood supply, genetics)
• Intestinal Polyps (genetics, metabolism, pathology)
• Intestine, Small (blood supply, metabolism)
• Intramolecular Oxidoreductases (genetics, physiology)
• Isoenzymes (genetics)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Precancerous Conditions (genetics, metabolism, pathology)
• Prostaglandin-E Synthases
• Protein Transport
• beta Catenin (metabolism)