title: The roles of thioredoxin in protection against oxidative stress-induced apoptosis in SH-SY5Y cells.
abstract: Using models of serum deprivation and 1-methyl-4-phenylpyridinium (MPP(+)), we investigated the mechanism by which thioredoxin (Trx) exerts its antiapoptotic protection in human neuroblastoma cells (SH-SY5Y) and preconditioning-induced neuroprotection. We showed that SH-SY5Y cells are highly sensitive to oxidative stress and responsive to both extracellularly administered and preconditioning-induced Trx. Serum deprivation and MPP(+) produced an elevation in the hydroxyl radicals, malondialdehyde and 4-hydroxy-2,3-nonenal (HNE), causing the cells to undergo mitochondria-mediated apoptosis. Trx in the submicromolar range blocked the observed apoptosis via a multiphasic protection mechanism that includes the suppression of cytochrome c release (most likely via the induction of Bcl-2), the inhibition of procaspase-9 and procaspase-3 activation, and the elevated level of Mn-SOD. The reduced form of Trx suppresses the serum-free-induced hydroxyl radicals, lipid peroxidation, and apoptosis, indicating that H(2)O(2) is removed by Trx peroxidase. The participation of Trx in preconditioning-induced neuroprotection is supported by the observation that inhibition of Trx synthesis with antisense oligonucleotides or of Trx reductase drastically reduced the hormesis effect. This effect of Trx-mediated hormesis against oxidative stress-induced apoptosis is striking. It induced a 30-fold shift in LD(50) in the MPP(+)-induced neurotoxicity.
authors.affiliation: Laboratory of Biochemistry, National Heart, Lung, and Blood Institute and the Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, Maryland 20892, USA.
authors.forename: Tsugunobu
authors.initials: T
authors.lastname: Andoh
authors.forename: P Boon
authors.initials: PB
authors.lastname: Chock
authors.forename: Chuang Chin
authors.initials: CC
authors.lastname: Chiueh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D015227:Lipid Peroxidation; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D018384:Oxidative Stress; D013482:Superoxide Dismutase / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism* / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D016895:Culture Media, Serum-Free; D003574:Cytochrome c Group; D016376:Oligonucleotides, Antisense; D013879:Thioredoxins; D013482:Superoxide Dismutase; C505407:CASP3 protein, human; C506433:CASP9 protein, human; C505409:Casp3 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases