title: Inhibition of p38 mitogen-activated protein kinase unmasks a CD30-triggered apoptotic pathway in anaplastic large cell lymphoma cells.
abstract: CD30, a non-death domain-containing member of the tumor necrosis factor receptor superfamily, triggers apoptosis in anaplastic large cell lymphoma cells. The CD30 signaling pathways that lead to the induction of apoptosis are poorly defined. Here, we show that the induction of apoptosis by CD30 requires concurrent inhibition of p38 mitogen-activated protein kinase, which itself is activated by engagement of CD30 with CD30 ligand. Treatment of anaplastic large cell lymphoma cells with CD30 ligand and pharmacologic inhibitors of p38 mitogen-activated protein kinase, but not with CD30 ligand or inhibitors alone, triggered the activation of caspase-8 and the induction of apoptosis. Caspase-8 activation occurred within a few hours (2.5-4 h) after receptor triggering, was unaffected by the neutralization of ligands for the death domain-containing receptors TNFR1, Fas, DR3, DR4, or DR5, but was abolished by the expression of a dominant-negative form of the adaptor protein FADD. Importantly, we show that expression of the caspase-8 inhibitor c-FLIP(S) is strongly induced by the CD30 ligand, and that this is dependent on the activation of p38 mitogen-activated protein kinase. Thus, we provide evidence that the induction of apoptosis by CD30 in anaplastic large cell lymphoma cells is normally circumvented by the activation of p38 mitogen-activated protein kinase. These findings have implications for CD30-targeted immunotherapy of anaplastic large cell lymphoma.
authors.affiliation: Tenovus Research Laboratory, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, United Kingdom.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Krysov
authors.forename: Tania F
authors.initials: TF
authors.lastname: Rowley
authors.forename: Aymen
authors.initials: A
authors.lastname: Al-Shamkhani
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D061945:Caspase Inhibitors; D002453:Cell Cycle / Q000187:drug effects; D053222:Fas Ligand Protein / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D006801:Humans; D017730:Ki-1 Antigen / Q000276:immunology / Q000494:pharmacology*; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D061945:Caspase Inhibitors; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; D017730:Ki-1 Antigen; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053219:Receptors, Tumor Necrosis Factor, Member 25; D047888:Receptors, Tumor Necrosis Factor, Type I; C105190:TNFRSF10A protein, human; C506033:TNFRSF25 protein, human; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D053181:Caspase 8