title: Molecular mechanism of violacein-mediated human leukemia cell death.
abstract: Violacein, a pigment isolated from Chromobacterium violaceum in the Amazon River, presents diverse biologic properties and attracts interest as a consequence of its antileukemic activity. Elucidation of the molecular mechanism mediating this activity will provide further relevant information for understanding its effects on the cellular physiology of untransformed cells and for considering its possible clinical application. Here, we show that violacein causes apoptosis in HL60 leukemic cells but is ineffective in this respect in other types of leukemia cells or in normal human lymphocytes and monocytes. Violacein cytotoxicity in HL60 cells was preceded by activation of caspase 8, transcription of nuclear factor kappaB (NF-kappaB) target genes, and p38 mitogen-activated protein (MAP) kinase activation. Thus, violacein effects resemble tumor necrosis factor alpha (TNF-alpha) signal transduction in these cells. Accordingly, infliximab, an antibody that antagonizes TNF-alpha-induced signaling abolished the biologic activity of violacein. Moreover, violacein directly activated TNF receptor 1 signaling, because a violacein-dependent association of TNF receptor-associated factor 2 (TRAF2) to this TNF receptor was observed in coimmunoprecipitation experiments. Hence, violacein represents the first member of a novel class of cytotoxic drugs mediating apoptosis of HL60 cells by way of the specific activation of TNF receptor 1.
authors.affiliation: Departamento de Bioquímica, Universidade Estadual de Campinas, Sao Paulo, Brazil.
authors.forename: Carmen Veríssima
authors.initials: CV
authors.lastname: Ferreira
authors.forename: Carina L
authors.initials: CL
authors.lastname: Bos
authors.forename: Henri H
authors.initials: HH
authors.lastname: Versteeg
authors.forename: Giselle Z
authors.initials: GZ
authors.lastname: Justo
authors.forename: Nelson
authors.initials: N
authors.lastname: Durán
authors.forename: Maikel P
authors.initials: MP
authors.lastname: Peppelenbosch
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020014:K562 Cells; D015473:Leukemia, Promyelocytic, Acute; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000378:metabolism; D020298:U937 Cells; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D015703:Antigens, CD; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D007211:Indoles; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; D015534:Trans-Activators; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; C063155:violacein