Studies on the Role of Protein Kinase C in Multistage Carcinogenesis and Their Relevance to Risk Extrapolation

One of the most intensively studied non-genotoxic carcinogens is the phorbol ester tumor promoter 12-0-tetradecanoylphorbol-13-acetate (TPA). Since TPA appears to exert its biologic effects through protein kinase C (PKC), a key enzyme in signal transduction, we have studied this enzyme in considerable detail. To explore the role of PKC in carcinogenesis we developed various types of cell lines that overproduce the PKC βI isoform. To gain further insight into the relationship between PKC structure and its function in tumor promotion we expressed deletion mutants of PKC βI in a rat fibroblast cell line. These studies provide genetic evidence that PKC plays a critical role in growth control and the action of certain growth factors, tumor promoters and oncogenes. The findings are discussed within the context of multistage carcinogenesis, risk assessment, and cancer prevention.