Nitric oxide-dependent pro-oxidant and pro-apoptotic effect of metallothioneins in HL-60 cells challenged with cupric nitrilotriacetate

Citation
Sx. Liu et al., Nitric oxide-dependent pro-oxidant and pro-apoptotic effect of metallothioneins in HL-60 cells challenged with cupric nitrilotriacetate, BIOCHEM J, 354, 2001, pp. 397-406
Citations number
48
Categorie Soggetti
Biochemistry & Biophysics
Journal title
BIOCHEMICAL JOURNAL
ISSN journal
02646021 → ACNP
Volume
354
Year of publication
2001
Part
2
Pages
397 - 406
Database
ISI
SICI code
0264-6021(20010301)354:<397:NOPAPE>2.0.ZU;2-D
Abstract
Intracellular safeguarding functions of metallothioneins (MTs) include sequ estering transition and heavy metals, scavenging free radicals and protecti ng against electrophiles. We report that MT protection against Cu-induced c ytotoxicity can be reversed and pro-oxidant and pro-apoptotic effects can b e induced in HL-60 cells exposed to NO. We demonstrate that in ZnCl2-pretre ated 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 cl usters caused loosening and release of redox-active Cu, enhanced redox-cycl ing activity of Cu and increased peroxidation of major classes of membrane phospholipids. We also found that Cu-induced oxidative stress in ZnCl2-pret reated/Cu-NTA-loaded HL-60 cells was accompanied by apoptosis documented by characteristic changes of nuclear morphology, internucleosomal DNA cleavag e, externalization of phosphatidylserine, release of cytochrome c from mito chondria into cytosol and activation of caspase-3. We conclude that in Cu-c hallenged cells, NO can reverse the protective role of MTs and convert them into pro-oxidant, pro-apoptotic implements.