Proteasome inhibitors induce mitochondria-independent apoptosis in human glioma cells

The proteasome inhibitors lactacystin and AcLLNal induced p53-independent apoptosis in two human glioma cell Lines, and the apoptosis was accompanied by up-regulation of immunoreactive wild-type p53, p21(Waf1), Mdm2, and p27(Kip1). Pretreatment with cycloheximide decreased the induction of cell death independently bf p53 protein status, suggesting that the upregulation of short-lived proteins is associated with proteasome inhibitor-induced apoptosis, Caspase-3-like proteases were activated in the proteasome inhibitor-mediated apoptosis, and the induction of cell death was inhibited more effectively in the presence of z-VAD.fmk than in the presence of Ac-DEVD.fmk, suggesting that caspases other than caspase-3 are involved. Nonetheless, there were no significant alterations in levels of immunoreactive Bcl-2, Bcl-x(L), Bas, Bad, and Ball, nor ally evidence of cytochrome c release into cytosol and dissipation of Delta Psi(m). Thus, the proteasome inhibitor-induced apoptosis is mediated by a mitochondria-independent mechanism, and the once activated caspase-3 does not cause the cytochrome c release and the Delta Psi(m) disruption, (C) 1999 Federation of European Biochemical Societies.