We have previously demonstrated that supplemental dietary Ursodeoxycholic Acid (UDCA) inhibited the development of azoxymethane-induced rat colonic tumors. To examine the mechanisms by which UDCA causes anticarcinogenic effects, studies in the application demonstrated that UDCA increased RasGTPase Activating Protein (RasGAP) activity and generated caspase-3 dependent RasGAP -N and -C terminal fragments. The important goal of this application is to determine whether RasGAP C-terminal fragment has a role in the inhibition and prevention of colon cancer. In cell culture studies we have demonstrated that RasGAP C-terminal fragment sensitizes colon cancer cells to UDCA dependent apoptosis. To evaluate the effect of RasGAP C-terminal fragment on tumor progression the growth of tumor xenografts stably transfected with this gene will be investigated. Further, the effect of Intratumoral delivery of permeable RasGAP C-fragment protein on tumor xenografts will be evaluated. To determine the chemopreventive efficacy of this fragment the effect of introduction of RasGAP C-cDNA through liposome enema on rectal aberrant crypt formation will be investigated. This will be the first attempt to evaluate in vivo the anti-cancer and chemopreventive efficacy of RasGAP C-terminal fragment in mouse models. We have also utilized innovative technologies in isolating RasGAP C-fragment protein attached to a HIV peptide, which permits its transport across cell membranes and liposome based gene delivery in mouse colon. Our rationale for these studies is that development of scientifically based evidence to support an anti-cancer and preventive benefit of RasGAP C-terminal fragment would provide a foundation for human studies to test potential benefits in cancer patients and high risk individuals. It is hoped that the information gained by this application can be exploited and applied toward the design of a more effective inhibitor for colon cancer prevention.
Summary Colorectal cancer (CRC) is a leading cause of cancer-related mortality in the United States and about 5% of US population will develop CRC in their lifetime. Ursodeoxycholic Acid (UDCA) is a bile acid, which is used in the treatment of liver diseases. We have shown that UDCA also prevents colon cancer in animal models. Human trials have confirmed the use of UDCA in CRC prevention. However, the exact mechanisms by which UDCA prevents CRC are not clearly understood. We have found that UDCA increases a specific protein in the colon cancer cells. In the presence of this protein, UDCA is more effective in the suppression of cancer growth. The proposed work will test this hypothesis in mouse models of CRC. If successful, this protein will help in creating new cancer drugs for colon cancer prevention.
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