Title

The impact of prostaglandin suppression on intestinal tumorigenesis

Date of Completion

January 2008

Keywords

Biology, Genetics|Health Sciences, Oncology

Degree

Ph.D.

Abstract

Prostaglandin E2 (PGE2) is a bioactive lipid that can elicit a wide range of biological effects associated with inflammation and cancer. PGE2 and other prostanoid species are derived from arachidonic acid (AA), which is rapidly metabolized by cyclooxygenase (COX) enzymes and subsequently converted into a panel of prostanoids by specific terminal synthases. Elevated levels of COX-2 and concomitant overproduction of PGE2 are often found in human colon adenomas and adenocarcinomas. These and other observations have led to the use of non-steroidal anti-inflammatory drugs (NSAIDs), including the selective COX-2 inhibitors, which has been shown in clinical trials to markedly reduce the relative risk of developing CRC by up to 40-50%. However, long-term clinical use of these agents is not without risk, as they have been associated with gastrointestinal toxicity and an increased risk of cardiovascular events. ^ Emerging concerns are directed to the fact that the exact mechanisms of NSAIDs have not been clearly understood. Therefore, the following studies were performed to better understand the impact of PG suppression in intestinal tumorigenesis by inhibiting COX-2, and also a PGE2 synthase, mPGES-1. We utilized a comparative global protein expression analysis on adenomas in ApcMin/+ mice before and after NSAID (sulindac) treatment. The two-dimensional protein expression maps and pair-wise analysis provided unique fingerprints of sulindac treatment, which can be used to identify a novel target of sulindac. In addition, the chemopreventive efficacy of targeting mPGES-1 was examined by using different mouse models. The mice deficient in mPGES-1 develop significantly fewer lesions in the intestines, which is shown to be associated with defects in tumor angiogenesis and also blocking β-catenin signaling. Furthermore, a humanized mouse model of mPGES-1 was used to test a novel mPGES-1 inhibitor, which also resulted in showing a reduction in the carcinogen-induced preneoplastic lesions. These studies provide new insights into the roles of PGE2 in the intestinal tumorigenesis, and also contribute largely to the development of a better chemopreventive agent. ^