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Genetic Deletion of mPGES-1 Suppresses Intestinal Tumorigenesis

¹ Center for Molecular Medicine and ² Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut; and ³ Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Merck Research Laboratories, Kirkland, Quebec, Canada

Requests for reprints: Daniel W. Rosenberg, Center for Molecular Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-3101. Phone: 860-679-8704; Fax: 860-679-7639; E-mail: Rosenberg{at}nso2.uchc.edu.

Key Words: Colorectal cancer • microsomal prostaglandin synthase-1 • nonsteroidal anti-inflammatory drugs • Apc, β-catenin

Elevated levels of prostaglandin E₂ (PGE₂) 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 PGE₂ synthase 1 (mPGES-1), which is responsible for generating PGE₂, 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 β-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 β-catenin in ACF, confirming that β-catenin is a critical target of PGE₂ 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]