EFFECTS OF HEXADECYLPHOSPHOCHOLINE ON PROTEIN-KINASE-C AND TPA-INDUCED DIFFERENTIATION OF HL60 CELLS

Several structural analogs of alkylphosphocholine (APC) were studied for their effects on protein kinase C (PKC) and 12-O-tetradecanoylphorbol-13-acetate (TPA) elicited biochemical and cellular events in HL60 cells. Hexadecylphosphocholine (He-PC2), the APC prototype, inhibited PKC competitively with respect to phosphatidylserine and noncompetitively with respect to CaCl2, both with an apparent K(i) of about 15-mu-M. Inhibition of PKC by He-PC2 was selective, since cyclic AMP dependent protein kinase and Ca2+/calmodulin dependent protein kinase II were relatively unaffected. He-PC2 inhibited TPA-induced depletion of PKC and TPA-stimulated phosphorylation of cellular proteins in HL60 cells. TPA-induced differentiation of HL60 cells was also inhibited by He-PC2, and this inhibition was synergistic or additive to the effects of 1-(5-isoquinoline-sulfonyl)-2-methylpiperazine (H-7), a PKC inhibitor. The present findings are consistent with the hypothesis that inhibition of PKC might be related, in part, to the antineoplastic effect of He-PC2 and ether lipid analogs such as ET-18-OCH3 (1-octadecyl-2-methyl-glycero-3-phosphocholine).