Nutritional Regulation of Catalase and Colorectal Cancer

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DESCRIPTION (provided by applicant) Susceptibility to cancer is influenced by dietary components. Indeed, diets rich in fat, nitrogen iron cause a high incidence of colorectal cancer, involve oxidative stress that impairs tumor suppressor function. Fiber-rich diets such as grain, vegetable and fruits, on the other hand, produce butyrate in the gut to suppress the incidence. Previous studies have postulated several roles for butyrate in the suppression of tumorigenesis, but it is still unclear how butyrate is linked to the regulation of oxidants and antioxidants. The researchers' preliminary data suggest that, upon its tyrosine phosphorylation, catalase binds Grb2 and Pl3Kp85, regulatory proteins of insulin signaling, and that catalase contains a consensus sequence of "suppressor of cytokine signaling" that enables it to bind elongin c, an essential factor for elongation of RNA synthesis. Importantly, butyrate induces catalase and suppresses its tyrosine phosphorylation and binding. Therefore, it is hypothesized that butyrate induces catalase and regulates an interaction of catalase with Grb2, Pl3Kp85 and elongin c to suppress hydrogen peroxide (H2O2) and its related damage, that would otherwise initiate and stimulate colorectal cancer. Thus, understanding the butyrate-dependent catalase regulation should provide new strategies to control colorectal cancer. To prove this hypothesis, the following aims are proposed: (1) Aim 1 is to determine the mechanisms of catalase binding with Grb2, Pl3Kp85, and elongin c, and the control by butyrate; (2) Aim 2 is to characterize the catalase that butyrate induces in human colorectal cancer cell line. To achieve these goals, the researchers will determine: (a) the binding sites of catalase whose mutation affects the complex formation, (b) the effects of butyrate on protein tyrosine kinase that phosphorylates catalase, (c) the binding-dependent alteration of catalase activity and oxidant-dependent p53 activation, and (d) the identities of catalase that butyrate induces; i.e., peroxisomal or cytosolic catalase. This study postulates a novel and innovative concept that catalase activity is modulated by a cell signaling- and intermolecular association-dependent mechanism. This research will allow the investigators to establish how butyrate regulates the catalase-activity and its binding with signaling molecules, that contribute to control cell mitogenesis and oxidant-dependent tumorigenesis.