title: Granzyme B induction signalling pathway in acute myeloid leukemia cell lines stimulated by tumor necrosis factor alpha and Fas ligand.
abstract: Acute myeloid leukemia (AML) cell lines treated by genotoxic agents or by Tumor Necrosis Factor alpha (TNFalpha) acquire potent cytotoxicity towards myeloid cells through activation of granzyme B (GrB)/perforin (PFN) system. Here we first extend this observation to another death receptor activator, Fas Ligand (FasL). Moreover, we analyzed GrB induction signalling pathway in TNFalpha- and FasL-stimulated AML cells. The effects of TNFalpha and FasL on GrB expression were specifically mediated by p38MAPK (Mitogen-activated-protein-kinase) activation. Otherwise, TNFalpha and FasL stimulation led to radical oxygen species (ROS) generation and ASK1 (Apoptosis-signal-regulating-kinase-1) activation. Endogenous activation of ASK1 by either H2O2 or thioredoxin (Trx) reductase inhibition had the same effects as TNFalpha and FasL on GrB up regulation. Altogether, our results suggest that TNFalpha- and FasL-stimulated AML cell lytic induction is regulated by a signalling pathway involving sequentially, ROS generation, Trx oxidation, ASK1 activation, p38MAPK stimulation and GrB induction at mRNA and protein levels.
authors.affiliation: INSERMU563/CPTP, Pavillon Lefebvre Bât B, Dpt G. DELSOL, Equipe G. LAURENT, CHU Purpan, 31024 Toulouse, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Guilloton
authors.forename: Christine
authors.initials: C
authors.lastname: Jean
authors.forename: Aurélie
authors.initials: A
authors.lastname: de Thonel
authors.forename: Guy
authors.initials: G
authors.lastname: Laurent
authors.forename: Anne
authors.initials: A
authors.lastname: Quillet-Mary
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D053222:Fas Ligand Protein / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053804:Granzymes / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D054353:Perforin; D006861:Hydrogen Peroxide; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D053804:Granzymes