title: Arecoline-induced death of human leukemia K562 cells is associated with surface up-modulation of TNFR2.
abstract: The goal of the present study is to explore the contribution of tumor necrosis factor-α (TNFα)-related pathway to the cytotoxicity of arecoline on human leukemia K562 cells. Arecoline treatment induced death of K562 cells and increased surface expression of TNFα, TNFR1, and TNFR2. Unlike that of TNFR1 mRNA, transcriptional levels of TNFα and TNFR2 mRNA increased in arecoline-treated cells. Moreover, arecoline-induced down-regulation of ADAM17 maturation was involved in surface up-modulation of TNFR1, TNFR2, and TNFα. Arecoline-elicited increase in intracellular Ca(2+) concentration was responsible for JNK/c-Jun pathway activation and ERK inactivation. Abolition of JNK/c-Jun pathway suppressed arecoline-induced increase in transcriptional level of TNFα and TNFR2 mRNA. TNFα and TNFR2 promoter luciferase activity and chromatin immunoprecipitating analyses revealed that c-Jun increasingly bound with TNFα and TNFR2 promoter upon arecoline treatment. Over-expression of constitutively active MEK1 abolished the effect of arecoline on suppressing ADAM17 maturation. Pretreatment with TNFR2 antibody abrogated arecoline-induced increased susceptibility of K562 cells for the cytotoxicity of TNFα and arecoline-induced cell death. Taken together, our data suggest that up-modulation of TNFR2 surface expression is associated with arecoline-induced death of K562 cells.
authors.affiliation: Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
authors.forename: Ying-Jung
authors.initials: YJ
authors.lastname: Chen
authors.forename: Long-Sen
authors.initials: LS
authors.lastname: Chang
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000873:Anthracenes / Q000378:metabolism; D001115:Arecoline / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D002614:Chelating Agents / Q000378:metabolism; D018679:Cholinergic Agonists / Q000494:pharmacology*; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D020014:K562 Cells / Q000187:drug effects* / Q000502:physiology; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D034622:RNA Interference; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000873:Anthracenes; D002614:Chelating Agents; D018679:Cholinergic Agonists; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; C432165:pyrazolanthrone; D001115:Arecoline; D004533:Egtazic Acid; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D051722:ADAM Proteins; D002118:Calcium