Bortezomib induces in HepG2 cells IkappaBalpha degradation mediated by caspase-8.
The present paper demonstrates that the proteasome inhibitor bortezomib, which behaves as an apoptotic agent in hepatoma HepG2 cells, caused in these cells a decrease in IkappaBalpha level and a consequent increase in NF-kappaB activity. The effect already appeared at 4 h of treatment and preceded the onset of apoptosis which was observed at 24 h. Our results demonstrate that bortezomib-induced IkappaBalpha degradation occurred in conjunction with the activation of caspase-8; moreover, the decrease in IkappaBalpha level was prevented in a dose-dependent manner by the addition of z-IETD, a specific inhibitor of caspase-8. Bortezomib caused the same effects in non-tumor Chang liver cells, which were not susceptible to the apoptotic effect of the drug. Our results also show that other proteases, such as caspase-3 and calpains, exerted only a limited effect on IkappaBalpha degradation. These findings suggest that caspase-8 can be involved in the control of IkappaBalpha level. In addition, the activation of caspase-8 can exert, at least in the first phase of treatment with bortezomib, a protective effect in both HepG2 and Chang liver cells, favouring the activation of the survival factor NF-kappaB.
Calvaruso
Giuseppe
G
Dipartimento di Scienze Biochimiche, Università degli Studi di Palermo, Policlinico, Palermo, Italy.
Giuliano
Michela
M
Portanova
Patrizia
P
De Blasio
Anna
A
Vento
Renza
R
Tesoriere
Giovanni
G
D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D053181:Caspase 8 / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D008099:Liver / Q000187:drug effects; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*
D001897:Boronic Acids; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011719:Pyrazines; D000072000:NF-KappaB Inhibitor alpha; D000069286:Bortezomib; D053181:Caspase 8