STIMULATION OF PROSTAGLANDIN-E(2) PRODUCTION AND INDUCTION OF SPECIFIC PROTEIN-SYNTHESIS IN RAT PERITONEAL-MACROPHAGES BY A TUMOR PROMOTER STAUROSPORINE

Staurosporine is a microbial anti-fungal alkaloid having potent inhibi tory activity on protein kinase C and is a non 12-O-tetradecanoylphorb ol-13-acetate-type tumor promoter in two-stage carcinogenesis experime nts in mouse skin. Effects of staurosporine and its structurally relat ed compounds K-252a, KT5720 and KT5822 on prostaglandin E2 production, release of arachidonic acid from membrane phospholipids, and uptake o f [S-35]methionine into intracellular proteins were examined in rat pe ritoneal macrophages. Among the four compounds, only staurosporine sti mulated the production of prostaglandin E2 and release of arachidonic acid at concentrations of 1 ng/ml and 10 ng/ml. The uptake of [S-35]me thionine into cellular proteins, estimated to be 120 kDa and 125 kDa m olecular mass, was also stimulated by staurosporine treatment, and the uptake was increased in parallel with the increase in prostaglandin E 2 production. At higher concentrations (100 ng/ml and 1000 ng/ml), sta urosporine inhibited prostaglandin E2 production and did not induce th e specific protein synthesis. Other compounds neither stimulated prost aglandin E2 production nor induced specific protein synthesis. K-252a inhibited prostaglandin E2 production at concentrations above 10 ng/ml . These results suggest that the staurosporine-induced proteins might participate in the tumor promotion or at least in the staurosporine-in duced stimulation of prostaglandin E2 production.