The effect of plant phenols on the expression and activity of phorbol ester-induced PKC in mouse epidermis

Protein kinase C (PKC) is thought to be a major intracellular receptor for the mouse skin tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). The diversity of PKC isoforms, and their central role in many signaling pathways, makes them important targets for potential chemopreventive agents. Our earlier studies showed that the plant phenols protocatechuic acid, chlorogenic acid and tannic acid alter the activity of enzymes involved in carcinogen activation, inhibit the formation of polycyclic aromatic hydrocarbon (PAH)-DNA adducts in mouse epidermis and decrease the level of lipid peroxidation in the epidermal microsomes. In the present study the effects of protocatechuic acid, chlorogenic acid and tannic acid on TPA-stimulated PKC isozymes alpha, beta(1), beta(2), gamma and zeta activity, and their distribution in mouse epidermis, was examined. The application of these phenolics 15 min before a single dose (3.4 nmol) of TPA resulted in significant inhibition of PKC translocation and a subsequent decrease in classical and novel/atypical PKC isoforms in comparison to a group of mice treated with TPA alone. The most potent inhibitor of PKC translocation and activity was tannic acid. This compound increased the levels of PKCalpha, beta(1), beta(2) in the cytosolic fraction by between 127% and 492% in comparison with TPA treated group of mice. Tannic acid decreased the activities of all three PKC classes by approximately 94% in the membrane fraction in comparison with the TPA treated group of animals. The effect of protocatechuic and chlorogenic acids on the distribution and activity of PKC isozymes was moderate. These compounds mostly affected translocation of PKCalpha and subsequently the activity of classical PKC. The enzyme activity in the particulate fraction was reduced by 59% and 43% in comparison with the TPA group, respectively. Thus, the results of these studies suggest that the subcellular distribution of PKC isoforms, and the activity of PKCs, can be modulated by plant phenolic acids, particularly tannic acid, and that such actions represent a part of the anti-promotional activity of these substances in mouse epidermis.