Mechanisms for Chemoprevention of Colorectal Cancer

Vanderbilt University, Nashville TN

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Abstract

[unreadable] DESCRIPTION (provided by applicant): There are several molecular pathways involved in the regulation of intestinal homeostasis and epithelial differentation that are important in a number of digestive diseases. Colorectal cancer is one such disease and is a major health concern in this country. One group of compounds found to decrease the risk of colorectal cancer is non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs are known to block production of a bioactive lipid, prostaglandin E2 (PGE2), that is derived from endoperoxide H2 synthase-1 and -2 [cyclooxygenase-1 (COX-1) and COX-2] enzymes. PGE2 is the most abundant prostaglandin in gastrointestinal tumors and can promote tumorigenesis by modulating apoptosis, proliferation, and angiogenesis. However, prolonged use of some NSAID agents is associated with unacceptable side effects (cardiovascular and gastrointestinal). Other potential targets for chemopreventative agents that modulate PGE2 levels include 15-hydroxyprostaglandin dehydrogenase (15-PGDH), which enzymatically degrades PGE2, and/or the prostaglandin transporter (PGT), which facilitates PGE2-movement across the plasma membrane. Our preliminary data indicate that 15-PGDH is down-regulated in colorectal cancer. We previously found that epidermal growth factor represses 15-PGDH expression in colorectal cancer cells through binding of a transcriptional represser, Snail, which binds to conserved E-box elements in the 15- PGDH promoter to inhibit transcription. However, our preliminary data also indicate that the 15-PGDH promoter is hypermethylated and epigenetically repressed by histone deactylases in colorectal cancers, suggesting that the mechanisms by which 15-PGDH is repressed in colorectal cancers remains poorly understood. Additionally, our data indicate that PGT may play an important role in preventing tumorigenesis, as our preliminary data show that PGT expression is reduced in colorectal cancers. We postulate that reactivation of prostaglandin metabolism by restoration 15-PGDH and PGT function may aid in the ability of cells to more appropriately regulate cell growth and viability. We propose the following specific aims to investigate these problems: 1) delineate the mechanisms which regulate decreased 15-PGDH expression in colorectal cancer; 2) characterize the role of PGT in colorectal cancer; and 3) investigate mechanisms by which PGT expression is repressed in colorectal cancer. This work will help to identify additional important targets for the prevention and/or treatment of colorectal cancer and may lead to the design of novel targeted therapies for treating colorectal cancers. It is becoming increasing apparent that the targeting of a single molecule will not be as effective as is needed to have a significant impact on this disease. [unreadable] [unreadable] [unreadable]