title: Superoxide-mediated early oxidation and activation of ASK1 are important for initiating methylglyoxal-induced apoptosis process.
abstract: Methylglyoxal (MG) is a physiological metabolite, but it is known to be toxic, inducing stress and causing apoptosis. Our previous studies demonstrated that MG induced apoptosis in Jurkat cells by activating the c-Jun N-terminal kinase (JNK) signal transduction pathway, which induced an obvious decrease in mitochondrial membrane potential, followed by caspase-3 activation. Here, we observed that MG-induced apoptosis was associated with both rapid production of superoxide anion (O(2)(-)) followed by a marked increase in ROS and striking and temporal activation of ASK1. Overexpression of wild-type ASK1 could enhance the rate of apoptosis induced by MG, whereas the expression of the kinase-inactive form of ASK1 notably prevented cells from MG-induced death. NAC and PDTC blocked the activation of ASK1 and MG-induced apoptosis completely. Moreover, nonthiol antioxidants SOD-mimic MnTBAP and catalase together obviously inhibited MG-induced ASK1 activation and apoptosis induction. Correspondingly, MG-mediated ASK1 activation was enhanced by diethyldithiocarbamate (DDC). Addition of antioxidant into the culture of cells at a later stage (4-8 h after the initial MG treatment) failed to prevent their death. These results suggest that activating ASK1 at the early stage linking to production of O(2)(-) is crucial for subsequent progression of apoptosis in MG-treated Jurkat cells.
authors.affiliation: Department of Immunology, Nagoya University School of Medicine, Aichi, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Du
authors.forename: H
authors.initials: H
authors.lastname: Suzuki
authors.forename: F
authors.initials: F
authors.lastname: Nagase
authors.forename: A A
authors.initials: AA
authors.lastname: Akhand
authors.forename: X Y
authors.initials: XY
authors.lastname: Ma
authors.forename: T
authors.initials: T
authors.lastname: Yokoyama
authors.forename: T
authors.initials: T
authors.lastname: Miyata
authors.forename: I
authors.initials: I
authors.lastname: Nakashima
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D051698:Activating Transcription Factor 2; D017209:Apoptosis / Q000187:drug effects*; D002374:Catalase / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004050:Ditiocarb / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D016166:Free Radical Scavengers / Q000494:pharmacology; D005982:Glutathione Transferase / Q000737:chemistry; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D019169:Jurkat Cells / Q000187:drug effects / Q000378:metabolism; D048670:MAP Kinase Kinase 4; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010084:Oxidation-Reduction; D010957:Plasmids; D011765:Pyruvaldehyde / Q000494:pharmacology*; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection
chemical_list: D051698:Activating Transcription Factor 2; D002614:Chelating Agents; D017362:Cyclic AMP Response Element-Binding Protein; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D013481:Superoxides; D011765:Pyruvaldehyde; D004050:Ditiocarb; D002374:Catalase; D013482:Superoxide Dismutase; D005982:Glutathione Transferase; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; C482858:MAP3K5 protein, human; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D000111:Acetylcysteine