Nonmutagenic mechanisms in carcinogenesis: role of protein kinase C in signal transduction and growth control.

There is accumulating evidence that the multistage carcinogenic process is associated with the progressive acquisition of mutations in cellular proto-oncogenes and in growth-suppressor genes. At the same time, several types of evidence indicate that nongenotoxic agents and epigenetic events also play an important role in the evolution of tumors. One of the most intensively studied nongenotoxic agents is the phorbol ester tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and related compounds. 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. Our strategy has been to perturb signal transduction by developing cell lines that overexpress the beta 1 isoform of PKC. Such derivatives of rat fibroblasts display alterations in morphology and growth factors, altered expression of c-myc, ornithine decarboxylase, and phorbin, and increased susceptibility to transformation by certain oncogenes, H-ras, myc, and fos. These findings provide direct genetic evidence that PKC plays a critical role in growth control and the action of certain growth factors, tumor promoters, and oncogenes. In related studies, we have characterized the beta 1 isoform that is overproduced in the above cell systems in terms of its biochemical, kinetic, and immunologic properties. The enzyme has several properties characteristic of native PKCs. A surprising finding is that c-H-ras-transformed derivatives of the cells that overexpress PKC beta 1 display a several-fold increase in the expression of the endogenous alpha 1 isoform of PKC and a decrease in the expression of the endogenous epsilon isoform.(ABSTRACT TRUNCATED AT 250 WORDS)