title: Extracellular signal-regulated kinase (ERK) activity is required for TPA-mediated inhibition of drug-induced apoptosis.
abstract: Leukemia cells respond to toxic stimuli by undergoing a form of programmed cell death known as apoptosis. However, the signaling events responsible for the execution of this form of death are poorly understood. Mitogen-activated protein kinase (MAPK) signaling cascades are involved in the cellular response to extracellular stimuli. Specifically, extracellular signal-regulated kinases (ERKs) have been associated with proliferation and differentiation, whereas the c-Jun N-terminal kinase/stress-activated protein kinases (JNK/SAPKs) have been implicated in cell arrest and death. We report the use of 12-O-tetradecanoylphorbol-13-acetate (TPA) in the inhibition of apoptosis in HL-60 cells stimulated with the JNK/SAPK activator anisomycin. This anti-apoptotic effect was accompanied by a sustained increase in ERK activity. Furthermore, the use of protein kinase C (PKC) inhibitors suggested that PKC was involved in the induction of ERK activity and in the inhibition of apoptosis by TPA since the inhibition of apoptosis was attenuated when cells were pretreated with PKC inhibitors. Lastly, we observed that the use of the MEK1 inhibitor PD98059 inhibited TPA-mediated ERK activity and abrogated the anti-apoptotic effects of TPA. However, apoptotic inhibition was not solely ERK-dependent since cells lacking JNK/SAPK stimulation did not undergo apoptosis. Therefore, we conclude that TPA inhibits the induction of apoptosis in anisomycin-treated HL-60 cells through an ERK-dependent pathway and that this effect can be reversed by the attenuation of ERK activity accompanied with the stimulation of JNK/SAPK activity.
authors.affiliation: Department of Physiology and Pharmacology, Comprehensive Cancer Center of Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina, 27157, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Stadheim
authors.forename: G L
authors.initials: GL
authors.lastname: Kucera
mesh_terms: D000841:Anisomycin / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D053938:DNA Fragmentation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D018922:HL-60 Cells / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D008301:Maleimides / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases; D009281:Naphthalenes / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D005419:Flavonoids; D007211:Indoles; D008301:Maleimides; D009281:Naphthalenes; D000841:Anisomycin; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C058819:calphostin C; C070515:bisindolylmaleimide I; D013755:Tetradecanoylphorbol Acetate; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one