Kitagawa H, Tani E, Ikemoto H, Ozaki I, Nakano A, Omura S
Department of Neurosurgery, Hyogo College of Medicine, Nishinomiya, Japan.
FEBS Lett. 1999 Jan 25;443(2):181-6. doi: 10.1016/s0014-5793(98)01709-8.
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, p21Waf1, Mdm2, and p27Kip1. 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 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.
蛋白酶体抑制剂乳胞素和AcLLNal在两种人类胶质瘤细胞系中诱导了不依赖p53的细胞凋亡，且该凋亡伴随着免疫反应性野生型p53、p21Waf1、Mdm2和p27Kip1的上调。用放线菌酮预处理可降低细胞死亡的诱导，且与p53蛋白状态无关，这表明短命蛋白的上调与蛋白酶体抑制剂诱导的细胞凋亡有关。在蛋白酶体抑制剂介导的细胞凋亡中，类似半胱天冬酶-3的蛋白酶被激活，并且在存在z-VAD.fmk时比在存在Ac-DEVD.fmk时更有效地抑制了细胞死亡的诱导，这表明除了半胱天冬酶-3之外的其他半胱天冬酶也参与其中。尽管如此，免疫反应性Bcl-2、Bcl-X(L)、Bax、Bad和Bak的水平没有显著变化，也没有任何细胞色素c释放到细胞质中以及线粒体膜电位消散的证据。因此，蛋白酶体抑制剂诱导的细胞凋亡是由一种不依赖线粒体的机制介导的，并且一旦激活的半胱天冬酶-3不会导致细胞色素c释放和线粒体膜电位破坏。
