Absence of Bax switched MG132-induced apoptosis to non-apoptotic cell death that could be suppressed by transcriptional or translational inhibition

被引:0
作者
Wen-Xing Ding
Hong-Min Ni
Xiao-Ming Yin
机构
[1] University of Pittsburgh School of Medicine,Department of Pathology
[2] University of Pittsburgh School of Medicine,Department of Pathology
来源
Apoptosis | 2007年 / 12卷
关键词
Proteasome inhibitor; MG132; ER stress; Ubiquitin aggregates; Vacuoles; Non-apoptotic cell death;
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学科分类号
摘要
Targeting to the ubiquitin proteasome degradation pathway has become a promising approach for treating cancer. Previous studies showed that inhibition of the proteasome can induce apoptosis in various cancer cells. However, whether and how the inhibition of the proteasome induces other forms of cell death is not quite known. We previously showed that proteasome inhibitors including MG132 and Bortezomib could induce apoptosis in a Bax- and caspase-dependent way. In the present study, we found that in the absence of Bax and caspase activation, inhibition of the proteasome could also kill cancer cells by an alternative, non-apoptotic form of cell death. We further demonstrated that proteasome inhibitors, such as MG132, could induce intracellular accumulation of polyubiquitinated proteins and extensive cellular vacuolization likely due to ER stress. Translational or transcriptional inhibitors suppressed MG132-induced polyubiquitinated protein accumulation, and in turn inhibited MG132-induced ER stress, cellular vacuolization and cell death. These findings thus suggested that non-apoptotic cell death was resulted from misfolded protein accumulation and ER stress. Furthermore, our study indicated that proteasome inhibitors could be favorable chemotherapeutic agents because they could induce non-apoptotic cell death in addition to apoptosis, which could overcome resistance due to compromised apoptotic machinery.
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页码:2233 / 2244
页数:11
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