Antiapoptotic response to induced GSH depletion: involvement of heat shock proteins and NF-kappaB activation.
Alteration of glutathione (GSH) homeostasis represents one of the earliest events during the commitment of stress-induced apoptosis. Extrusion of GSH into the extracellular milieu, in response to several oxidative stimuli, has been suggested as a molecular switch triggering apoptosis. However, chemical depletion of GSH does not induce cell death even though cytochrome c release from mitochondria has been observed. Here we report that U937 cells treated with buthionine sulfoximine (BSO) are able to survive and to inhibit the apoptotic program downstream of cytochrome c release. BSO treatment induces a highly significant decrease of GSH in both the cytosolic and mitochondrial fractions. The concomitant release of cytochrome c into the cytosol was associated with nuclear translocation of apoptosis-inducing factor. GSH depletion also resulted in reactive oxygen species production and in a specific increase of mitochondrial protein carbonyls. However, all these events were transiently present inside cells and efficiently counteracted by cell-repairing systems. We observed an increase in the proteasome activity and in the expression levels of heat shock protein 27 (Hsp27) and Hsp70. Moreover, nuclear factor-kappaB (NF-kappaB) was activated in our system as a survival cell response against the oxidative injury. Overall results suggest that activation of NF-kappaB and Hsp could allow cell adaptation and survival under exhaustive GSH depletion.
Filomeni
Giuseppe
G
Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133 Rome, Italy.
Aquilano
Katia
K
Rotilio
Giuseppe
G
Ciriolo
Maria R
MR
D017209:Apoptosis; D051033:Apoptosis Inducing Factor; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D005420:Flavoproteins / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D020298:U937 Cells
C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; D005420:Flavoproteins; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D019328:Buthionine Sulfoximine; D045304:Cytochromes c; D005978:Glutathione