Absence of Bax switched MG132-induced apoptosis to non-apoptotic cell death that could be suppressed by transcriptional or translational inhibition.
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.
Ding
Wen-Xing
WX
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. wed1@pitt.edu
Ni
Hong-Min
HM
Yin
Xiao-Ming
XM
D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000473:pathology; D045325:HCT116 Cells; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology*; D009336:Necrosis; D025821:Polyubiquitin / Q000378:metabolism; D061988:Proteasome Inhibitors; D014176:Protein Biosynthesis / Q000187:drug effects*; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D014158:Transcription, Genetic / Q000187:drug effects*; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000172:deficiency*
D007976:Leupeptins; D061988:Proteasome Inhibitors; D051028:bcl-2-Associated X Protein; D025821:Polyubiquitin; D003609:Dactinomycin; D000255:Adenosine Triphosphate; D003513:Cycloheximide; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde