CANCER PREVENTION & IMBALANCE IN PROTEIN PHOSPHORYLATION

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The long term goal of this study is to test a hypothesis that oxidants may induce an imbalance in protein phosphorylation systems, and chemopreventive antioxidants may counteract this process. Oxidants have emerged as important mediators of tumor promotion in one era of carcinogenesis research while protein kinase C (PKC) and protein phosphatase (PP) 1 and 2 A have emerged as receptors for tumor promoters in another. Nonetheless, the interlink between these mediators is poorly understood. Our preliminary studies revealed that oxidant tumor PP2A are susceptible to oxidative inactivation, oxidant tumor promoters may induce compartmentalization and imbalance in the PKC, PP1/PP2A system. Conversely, chemopreventive antioxidants may disrupt the cross- talk between the oxidants and the receptors for tumor promoters. These studies will be carried out with the C3H/10T1/2 cell line and an in vitro model of transformation. The primary focus is to understand the direct and indirect actions of oxidants that influence the PKC/PP system and its direct counteraction by antioxidants (indirect actions). Transformation- related studies will be restricted to induction of ornithine decarboxylase, c-fos, c-myc and in vitro scoring of the transformed foci. The first aim is to determine whether the oxidant tumor promoters H202, benzoyl peroxide and phorbol ester-induced oxidants can induce an imbalance or compartmentalization in PKC/PP. Then, studies are extended to understand how the imbalance in PKC/PP could affect the above mentioned transformation-related events. The second aim is to determine the abilities of nonsulfur chemopreventive agents, carotenoids (lycopene, Beta-carotene), vitamin E, and ellagic acid to counteract the oxidant effects on PKC, PP1, and PP2A. The third aim is to extend these studies to the organosulfur compounds diallysulfide and oltipraz (dithiolthiones) to assess whether the antioxidant actions of sulfur agents differ from that of nonsulfur agents. The final aim is to understand the interactions of chemopreventive agents that are effective in counteracting tumor promoters. The combination of selenium, vitamin E, Vitamin C, and diallylsulfide will be studied. The results of these studies may further help understand the molecular mechanisms involved in cancer chemoprevention.