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 B-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 B-catenin in ACF, confirming that B-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. [Cancer Res 2008;68(9):3251-9]

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

“…As demonstrated in a study by Nakanishi et al (2008), we have herein found that AOM-induced pre-neoplastic ACF formation in an early phase of colon carcinogenesis was suppressed by the lack of mPGES-1, with a reduction in the number of large ACF (Figure 4). In addition, we further found that the formation of large ACF was enhanced by transgenic overexpression of mPGES-1, although spontaneous colon carcinogenesis did not occur.…”

“…In this study, we found that mPGES-1 deficiency suppresses chemical carcinogen-induced colon Figure 1, genetic deletion of mPGES-1 significantly reduced both the total number and size of polyps in the colon after AOM administration. Nakanishi et al (2008) also recently reported that the introduction of mPGES-1 gene deletion onto Apc D14/ þ mice, in which spontaneous intestinal and colon carcinogenesis occurred, reduced the number and size of polyps. Taken together with this previous report, this study has provided additional lines of evidence that mPGES-1-derived PGE 2 promotes multiple steps in colon carcinogenesis.…”

PGE2-Associated Inflammation and Gastrointestinal Tumorigenesis

“…Consistently, disruption of the mPGES-1 gene also suppressed intestinal polyposis in other Apc gene mutant mice (Nakanishi et al 2008). Moreover, blocking PGE 2 signaling through the EP2 receptor led to significant suppression of polyp formation in Apc ∆716 mice (Sonoshita et al 2001).…”

Expression and Significance of Microsomal Prostaglandin Synthase-1 (mPGES-1) and Beclin-1 in the Development of Prostate Cancer

“…So inhibiting the expression of mPGES-1 may be a potential therapeutic target in clinical practice (Murakami et al, 2000). Nakanishi has demonstrated that genetic deletion of mPGES-1 could suppress intestinal and lung tumorigenesis in vivo animal trials (Nakanishi et al, 2008;Pecchi et al, 2008). Cheng et al (2006) has reported that mPGES-1 inhibitor could block PGE2 and make therapeutic effects in many diseases instead of nonsteroidal anti-inflammatory drugs (NSAIDs), meanwhile, no obvious side effects were observed.…”