Nuclear Hormone Receptor in Intestinal Biology

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DESCRIPTION (provided by applicant): There are several molecular signaling pathways involved in the regulation of intestinal homeostasis and epithelial differentiation 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). However, prolonged use of some of these agents is associated with unacceptable side effects (cardiovascular and gastrointestinal). Thus, it is crucial to develop more effective preventive measures with minimal toxicity and maximum benefit. Peroxisome proliferator-activated receptors (PPARs) are potential targets for chemopreventive agents. There are three PPAR isoforms, PPARa, PPARd, and PPAR?, which belong to the nuclear hormone receptor superfamily. Preliminary data indicates that a PPARd agonist promotes intestinal adenoma growth, increases tumor cell survival and induces angiogenesis. Since at least one PPARd agonist is currently under clinical evaluation for treatment of dyslipidemias and obesity, our results raise serious concerns about the use of these agents in people at high risk for colorectal cancer. Our preliminary data also indicate that activation of PPARd inhibits the ability of PPAR? to induce tumor cell death in vitro. We postulate that inhibition of PPARd may restore the ability of PPAR? agonists to induce apoptosis in vivo. We have recently identified a nuclear receptor NR4A2 which is a novel PGE2-regulated gene. NR4A2 is a nuclear receptor known to be involved in regulating brain function. We found that NR4A2 is elevated in human colorectal cancers and mediates the PGE2-induced activation of PPARd transcriptional activity by directly interacting with PPARd. However, the mechanisms by which NR4A2 modulates PPARd transcriptional activity during colorectal carcinogenesis are not clear. We propose the following specific aims to investigate these problems: 1) investigate mechanisms by which PPARd accelerates intestinal polyp growth and characterize PPARd target genes that control tumor growth; 2) characterize the role of PPARd in modulating the antitumor effects of PPAR? in colorectal cancer; and 3) delineate the mechanisms by which other nuclear receptors such as NR4A2 regulate PPARd transactivation. The results of the experiments proposed here may lead to the design of novel approaches for prevention and/or treatment of colorectal cancer.