) Continued elucidation of the genetics of human colorectal cancer has led to the identification of the adenomatous polyposis cell (APC) gene as the putative """"""""gatekeeper"""""""" of colorectal carcinogenesis. Mutations in the APC gene are present in approximately 80 percent of sporadic colon tumors and provide the molecular basis for the familial adenomatous polyposis (FAP) syndrome. Although the mechanism by which mutant APC causes colorectal tumors remains under intense investigation, the APC/Beta-catenin pathway represents an ideal molecular target for chemopreventive intervention. The chemopreventive activity of sulindac sulfone (FGN-1) in FAP patients has led to its consideration by the FDA as the first nonsurgical therapy for this disease. The hypothesis of the proposed studies is that FGN-1 induces apoptosis by restoring the activity of a malfunctioned APC/Beta-catenin pathway. Support for this hypothesis is provided by preliminary data which suggest that FGN-1 can modulate both Beta-catenin and its downstream target cyclin D1. Four human colon carcinoma cell lines bearing defined mutations in Beta-catenin and/or APC will be utilized in the proposed studies. The effect of FGN-1 on the transcription, translation and functional interaction of APC, Beta-catenin, GSK3Beta and Axin will be determined. The ability of FGN-1 to modulate both Beta-catenin-regulated transcription and downstream targets of the APC pathway will be evaluated. Elucidation of the biochemical and molecular pathways altered by FGN-1 will facilitate both the development of biomarkers of FGN-1 activity and the identification of compounds that may be more efficacious in preventing tumor formation. The proposed training plan has been designed to provide the applicant with the technical skills and educational background she requires to become an independent investigator in the area of chemoprevention. The applicant's background in nutritional biochemistry when combined with the proposed training in cancer prevention and molecular genetics will provide her with the unique ability to develop both natural and synthetic compounds as clinical chemopreventive agents
| Chang, Wen-Chi L; Everley, Lynette C; Pfeiffer 2nd, Gordon R et al. (2005) Sulindac sulfone is most effective in modulating beta-catenin-mediated transcription in cells with mutant APC. Ann N Y Acad Sci 1059:41-55 |
