简介

Protein kinase C in cancer chemoprevention My laboratory is interested in understanding the oxidative regulation of protein kinase C (PKC) and protein phosphatases (type 1 and 2A) by tumor promoters, and the counter regulation by dietary chemopreventive agents and anti-metastatic drugs. Work from this laboratory has demonstrated that oxidant tumor promoters by activating PKC and simultaneously inactivating protein phosphatases can induce an imbalance in protein phosphorylation. Rapid multiwell filtration methods have been developed to determine the activities of PKC and various protein phosphatases. These methodologies gave us the edge to study both protein kinases and phosphatases simultaneously. Since PKC is a receptor for diverse structurally unrelated tumor promoters as well as involved in growth regulation, it is a logical target site for the action of antitumor promoters and antiproliferative agents. Among many natural products screened, calphostin C, hypericin, and chelerythrine have emerged as specific inhibitors for PKC. Our recent studies have demonstrated an involvement of the site-specific oxidations or alkylating mechanisms in the action of these agents. This further emphasized the functional role for unique thiol-rich regions in both regulatory(zinc finger) and catalytic domains of PKC. Currently the studies are in progress to elucidate mechanisms of actionof chemopreventive agents such as selenium, vitamin E succinate, and organosulfur agents from vegetables. These studies are carried out using PKC isoenzymes isolated from rat brain and also using recombinant PKC in which cysteine residues are substituted by site-directed mutagenesis. Another area of interest is to understand the role of tumor promoters in cancer metastasis in addition to their known role in tumor promotion. Compared to experimental tumor promoters, phorbol esters, the oxidant-generating tumor promoters present in the tobacco smoke induced a stronger stimulation of metastasis of tumor cells at least in part by activating PKC. In view of inhibition of metastasis by structurally diverse inhibitors of PKC, this enzyme may be targeted for the design and development of anti-metastatic drugs. These studies are carried out using both in vitro and in