Activation of signaling pathways in HL60 cells and human neutrophils by farnesylthiosalicylate.
Effects of the farnesylcysteine mimetic, farnesylthiosalicylate on the activation of myeloid cells were studied. In dimethyl-sulfoxide-differentiated HL60 cells and in human neutrophils farnesylthiosalicylate (< or = 20 microM) dose-dependently elevated cytosolic Ca2+ concentrations, suggesting phospholipase-C-mediated release of the ion from intracellular stores. In human neutrophils, in addition to the production of inositol trisphosphate, farnesylthiosalicylate induced activation of the NADPH oxidase and translocation of the cytosolic oxidase components p47-phox and p67-phox to the membrane. The calcium signal, inositol-trisphosphate production and superoxide generation elicited by farnesylthiosalicylate were partially blocked by treatment of the cells with pertussis toxin, consistent with participation of pertussis-toxin-sensitive and pertussis-toxin-resistant elements. In HL60 cells, farnesylthiosalicylate (< or = 20 microM) did not activate NADPH oxidase but dose-dependently augmented PMA-elicited activity of the enzyme. This effect was resistant to pertussis-toxin treatment. In vitro augmentation of PKC-mediated phosphorylation of histone and cytosolic p47-phox by farnesylthiosalicylate and the finding that downregulation of PKC abrogated potentiation of NADPH oxidase activity by farnesylthiosalicylate were compatible with the involvement of PKC in the response of HL60 cells to farnesylthiosalicylate. It is suggested that the effects of farnesylthiosalicylate on myeloid cells reflect interaction of the analog with prenylcysteine-docking sites on cellular signaling elements.
Tisch
D
D
Department of Biochemistry, Faculty of Life Sciences, Tel Aviv University, Israel.
Halpern
M
M
Marciano
D
D
Kloog
Y
Y
Aviram
I
I
D002118:Calcium / Q000378:metabolism; D002451:Cell Compartmentation; D003545:Cysteine / Q000031:analogs & derivatives / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005204:Farnesol / Q000031:analogs & derivatives* / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000502:physiology; D018922:HL-60 Cells / Q000502:physiology*; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D009504:Neutrophils / Q000502:physiology*; D037342:Pertussis Toxin; D010740:Phospholipases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D016897:Respiratory Burst / Q000187:drug effects*; D012459:Salicylates / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D019311:Staurosporine / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D004791:Enzyme Inhibitors; D012459:Salicylates; D010566:Virulence Factors, Bordetella; C093323:farnesylthiosalicylic acid; D013481:Superoxides; D005204:Farnesol; C057785:S-farnesylcysteine; D015544:Inositol 1,4,5-Trisphosphate; D019255:NADPH Oxidases; D037342:Pertussis Toxin; D011493:Protein Kinase C; D010740:Phospholipases; D019204:GTP-Binding Proteins; D019311:Staurosporine; D003545:Cysteine; D002118:Calcium