Differential effects of suramin on protein kinase C isoenzymes. A novel tool for discriminating protein kinase C activities.

Suramin, a hexasulfonated naphthylurea, is known to induce differentiation and inhibit proliferation, angiogenesis, and development of tumors. It has also been shown to suppress the activity of the protein kinase C (PKC) isoenzymes alpha, beta, and gamma. Here we report on a differential effect of suramin on PKCmu and various PKC isoforms representing the cPKC, nPKC, and aPKC group of the PKC family. In the absence of any cofactors suramin activates all PKC isoforms in the order of aPKCzeta >> PKCmu > cPKC, nPKCdelta. As judged by the Vmax/KM ratios (0.5 for PKCmu and 2.2 for PKCzeta) the substrate syntide 2 is phosphorylated by suramin-activated PKCzeta around four times more effectively than by suramin-activated PKCmu. Suramin-activated PKCmu behaves like that activated by phosphatidylserine and the phorbol ester TPA regarding autophosphorylation and differential inhibition by the PKC inhibitors Gö 6976 and Gö 6983. In the presence of activating cofactors, such as phosphatidylserine and TPA or cholesterol sulfate (for PKCzeta), the activity of the aPKCzeta is further stimulated, PKCmu is not significantly affected, and the cPKCs and the nPKCdelta are strongly inhibited by suramin. The differential action of suramin on PKC isoenzymes might play a role in some of its biological effects, as for instance inhibition of proliferation and tumor development. Moreover, due to this property suramin will possibly be a valuable tool for discriminating the activities of PKC isoenzymes in vitro and in vivo.