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Proteasome inhibitors induce mitochondria‐independent apoptosis in human glioma cells
Author(s) -
Kitagawa Hiroyuki,
Tani Eiichi,
Ikemoto Hideyasu,
Ozaki Isao,
Nakano Atsuhisa,
Omura Satoshi
Publication year - 1999
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(98)01709-8
Subject(s) - lactacystin , apoptosis , cytochrome c , proteasome , cycloheximide , caspase , proteasome inhibitor , programmed cell death , intrinsic apoptosis , microbiology and biotechnology , mitochondrion , biology , apoptosome , cytosol , proteases , biochemistry , enzyme , protein biosynthesis
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 of p53 protein status, suggesting that the up‐regulation 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 , Bax, Bad, and Bak, nor any evidence of cytochrome c release into cytosol and dissipation of Δ Ψ 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 Δ Ψ m disruption.