Antiapoptotic response to induced GSH depletion:: Involvement of heat shock proteins and NF-κB activation

被引:41
作者
Filomeni, G [1 ]
Aquilano, K [1 ]
Rotilio, G [1 ]
Ciriolo, MR [1 ]
机构
[1] Univ Roma Tor Vergata, Dept Biol, I-00133 Rome, Italy
关键词
D O I
10.1089/ars.2005.7.446
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页码:446 / 455
页数:10
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