Nitric oxide-dependent pro-oxidant and pro-apoptotic effect of metallothioneins in HL-60 cells challenged with cupric nitrilotriacetate
| Autor: | Liu, S, Kawai, K, Tyurin, V A, Tyurina, Y Y, Borisenko, G G, Fabisiak, J P, Quinn, P J, Pitt, B R, Kagan, V E |
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| Jazyk: | angličtina |
| Rok vydání: | 2001 |
| Předmět: |
Nitrilotriacetic Acid
Caspase 3 Penicillamine Electron Spin Resonance Spectroscopy Apoptosis Cytochrome c Group HL-60 Cells DNA Fragmentation Nitric Oxide Oxidants Enzyme Activation Chlorides Zinc Compounds Caspases Carcinogens Organometallic Compounds Humans Metallothionein Nitric Oxide Donors Lipid Peroxidation Annexin A5 Oxidation-Reduction Chromatography High Pressure Liquid Phospholipids Research Article |
| Popis: | Intracellular safeguarding functions of metallothioneins (MTs) include sequestering transition and heavy metals, scavenging free radicals and protecting against electrophiles. We report that MT protection against Cu-induced cytotoxicity can be reversed and pro-oxidant and pro-apoptotic effects can be induced in HL-60 cells exposed to NO. We demonstrate that in ZnCl(2)-pretreated HL-60 cells loaded with copper nitrilotriacetate (Cu-NTA), exposure to an NO donor, S-nitroso-N-acetyl penicillamine, resulted in S-nitrosylation and oxidation of MT cysteines. This disruption of MT Cu-binding thiolate clusters caused loosening and release of redox-active Cu, enhanced redox-cycling activity of Cu and increased peroxidation of major classes of membrane phospholipids. We also found that Cu-induced oxidative stress in ZnCl(2)-pretreated/Cu-NTA-loaded HL-60 cells was accompanied by apoptosis documented by characteristic changes of nuclear morphology, internucleosomal DNA cleavage, externalization of phosphatidylserine, release of cytochrome c from mitochondria into cytosol and activation of caspase-3. We conclude that in Cu-challenged cells, NO can reverse the protective role of MTs and convert them into pro-oxidant, pro-apoptotic implements. |
| Databáze: | OpenAIRE |
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