Inhibition of chemotactic peptide-induced phosphoinositide hydrolysis by phorbol esters through the activation of protein kinase C in differentiated human leukemia (HL-60) cells.
Phorbol-12,13-dibutyrate (PDBU), a tumor-promoting and protein kinase C-activating phorbol ester, inhibited formylmethionylleucyl-phenylalanine-induced generation of inositol mono-, bis-, and tris-phosphates from the hydrolysis of phosphoinositides in human leukemia (HL-60) cells, which had been differentiated to polymorphonuclear leukocyte-like cells by pretreatment with dibutyryl cyclic adenosine 3':5'-monophosphate. PDBU did not alter the binding of formylmethionylleucyl-phenylalanine to the cells. Other protein kinase C-activating substances such as 12-O-tetradecanoylphorbol-13-acetate and 1-oleoyl-2-acetyl-glycerol could substitute for PDBU, but 4 alpha-phorbol-12,13-didecanoate, which is inactive for both tumor promotion and protein kinase C activation, was ineffective in this capacity. Prolonged treatment of the cells with PDBU resulted in the down-regulation and decrease of protein kinase C activity to the level of 30-40% of that in the control cells. In the down-regulated cells, formylmethionylleucylphenylalanine still induced generation of the phosphorylated inositols to the same extent as that in the control cells, but the inhibition of this reaction by PDBU was reduced to 30-50% as compared with that in the control cells. These results strongly suggest that tumor-promoting phorbol esters inhibit the agonist-induced phosphoinositide hydrolysis through the activation of protein kinase C in the differentiated HL-60 cells.
D002454:Cell Differentiation; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism*; D007942:Leukemia, Experimental / Q000378:metabolism* / Q000473:pathology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000037:antagonists & inhibitors*; D015240:Phorbol 12,13-Dibutyrate; D010703:Phorbol Esters / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D013403:Sugar Phosphates / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D007295:Inositol Phosphates; D010703:Phorbol Esters; D010716:Phosphatidylinositols; D013403:Sugar Phosphates; D015240:Phorbol 12,13-Dibutyrate; D009240:N-Formylmethionine Leucyl-Phenylalanine; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate