Diet is known to play important roles in influencing the development of human cancer, but the mechanisms are not well understood. The objective of this planning grant is to organize a multidisciplinary collaborative program to investigate the molecular mechanisms by which certain dietary constituents inhibit carcinogenesis. Our collaborative program will consist of investigators with demonstrated expertise in nutrition, carcinogenesis, molecular genetics, and signal transduction. We plan to select catechins, caffeine, and curcumin as the main dietary chemicals for mechanistic investigations. These compounds occur widely in fruits, beverages, or spices, and their cancer preventive activities have been demonstrated in animal models. It would be important to elucidate in depth their mechanisms of action and to determine whether these mechanisms are relevant in human cancer prevention. We plan to focus our studies on skin and colon cancers. Well established animal models and new transgenic mouse models, as well as relevant cell lines will be used. Our hypothesis is that catechins, caffeine, and curcumin suppress carcinogenesis by one or more of the following mechanisms: inhibition of inflammation, cell proliferation, cell transformation, and angiogenesis, and induction of apoptosis. We will study the key signaling and metabolic pathways leading to these processes, such as MAP-kinase, AP-1, Nfr,Kappa B,p53, and arachidonic acid metabolism. We will use DNA microarray and proteomic approaches to study multiple genetic pathways. A key feature of our program is to integrate studies in animal models, cell lines, and humans. Cell line studies will generate hypotheses on possible mechanisms of chemoprevention, and the hypotheses will be tested in animal models and humans. It would be important to elucidate the chemopreventive mechanisms most relevant to humans. We plan to create a structure to facilitate effective communication and interactions among the collaborators. A web-site is being set up to pool and share information and research results. We plan to establish facility Cores to facilitate the research. Monthly meetings and workshops among the investigators will be scheduled to design strategies and make study plans for the U54 application.
