Gamma-glutamyl transpeptidase activity mediates NF-kappaB activation through lipid peroxidation in human leukemia U937 cells.
Gamma-glutamyl transpeptidase (GGT) is a key enzyme in the catabolism of glutathione (GSH). Recently, it has been reported that the extracellular cleavage of GSH by GGT induced the production of reactive oxygen species (ROS), suggesting that GGT plays a pro-oxidant role. In the present study, we investigated the nature of the oxidative stress generate by glutathione and GGT and the possibility that this stress affects the activity of NF-kappaB a prototypical oxidant-stress-responsive transcription factor. We found that, in the presence of iron, a natural substrate of GGT, glutathione induces lipid peroxidation in U937 cells. This induction depends on GGT activity as it is prevented by the Serine/Borate complex, a GGT inhibitor. We found that y-glutamyl transpeptidase activity induces NF-kappaB DNA binding activity, an effect which is significantly reduced by the addition of GGT inhibitors (Serine/Borate complex and Acivicin). Moreover, we show that lipid peroxidation is involved in GGT-dependent NF-kappaB activation since vitamin E, which completely inhibits GGT-induced generation of lipid peroxides, prevents the GGT-dependent NF-kappaB activation. Finally, inhibition of GGT by either the Serine/Borate complex or by Acivicin resulted in cell apoptosis. This finding suggests that GGT-mediated NF-kappaB activation plays a role in the control of apoptosis in U937 cells.
Djavaheri-Mergny
Mojgan
M
INSERM U365, Institut Curie, Section de recherche, Paris, France. Mojgan.Mergny@curie.fr
Accaoui
Marie-José
MJ
Rouillard
Dany
D
Wietzerbin
Juana
J
D017209:Apoptosis / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008054:Lipid Peroxides / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D020298:U937 Cells; D014810:Vitamin E / Q000494:pharmacology; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*
D004791:Enzyme Inhibitors; D007555:Isoxazoles; D008054:Lipid Peroxides; D016328:NF-kappa B; D014810:Vitamin E; D004247:DNA; D005723:gamma-Glutamyltransferase; D005978:Glutathione; C006303:acivicin