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12-O-Tetradecanoyl Phorbol 13-Acetate, Protein Kinase C (PKC) Activator, Protects Human Leukemia HL-60 Cells from Taxol-Induced Apoptosis: Possible Role for Extracellular Signal-Regulated Kinase

Abstract The purpose of this study was to evaluate whether the mitogen-activated protein kinase / extracellular signal-regulated kinase (MEK) signaling pathway contributes to 12-O-tertadecanoyl phorbol 13-acetate (TPA)mediated protection from taxol-induced apoptosis of human leukemia HL-60 cells. Treatment of cells with taxol for 12 h resulted in apoptosis of HL-60 cells. TPA was protective against taxol-induced apoptosis and this anti-apoptotic effect was reversible when TPA was used in conjunction with staurosporine and H-7, PKC inhibitors, suggesting that TPA may protect HL-60 cells against taxol-induced apoptosis via the PKC-dependent pathway. Since TPA stimulates MEK signal transduction pathway in HL-60 cells, we postulated that MEK pathway may be playing a role in the ability of TPA to inhibit taxol-induced apoptosis. PD098059, a specific MEK kinase inhibitor, abolished the ability of TPA to inhibit taxol-induced apoptosis. These results suggest that activation of PKC in HL-60 cells confers protection against taxol-induced apoptosis and that MEK mediates anti-apoptotic signaling of PKC.