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

Wen Xing Ding, Hong Min Ni, Xiao-Ming Yin

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2233-2244
Number of pages12
JournalApoptosis
Volume12
Issue number12
DOIs
StatePublished - Dec 2007
Externally publishedYes

Fingerprint

Cell death
Proteasome Endopeptidase Complex
Cell Death
Proteasome Inhibitors
Apoptosis
Caspases
Cells
Neoplasms
Proteins
Ubiquitin
Machinery
Chemical activation
benzyloxycarbonylleucyl-leucyl-leucine aldehyde
Degradation

Keywords

  • ER stress
  • MG132
  • Non-apoptotic cell death
  • Proteasome inhibitor
  • Ubiquitin aggregates
  • Vacuoles

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Cell Biology

Cite this

Absence of Bax switched MG132-induced apoptosis to non-apoptotic cell death that could be suppressed by transcriptional or translational inhibition. / Ding, Wen Xing; Ni, Hong Min; Yin, Xiao-Ming.

In: Apoptosis, Vol. 12, No. 12, 12.2007, p. 2233-2244.

Research output: Contribution to journalArticle

@article{0b7153619f7e45829015408ccbcec132,
title = "Absence of Bax switched MG132-induced apoptosis to non-apoptotic cell death that could be suppressed by transcriptional or translational inhibition",
abstract = "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.",
keywords = "ER stress, MG132, Non-apoptotic cell death, Proteasome inhibitor, Ubiquitin aggregates, Vacuoles",
author = "Ding, {Wen Xing} and Ni, {Hong Min} and Xiao-Ming Yin",
year = "2007",
month = "12",
doi = "10.1007/s10495-007-0142-0",
language = "English (US)",
volume = "12",
pages = "2233--2244",
journal = "Apoptosis : an international journal on programmed cell death",
issn = "1360-8185",
publisher = "Springer Netherlands",
number = "12",

}

TY - JOUR

T1 - Absence of Bax switched MG132-induced apoptosis to non-apoptotic cell death that could be suppressed by transcriptional or translational inhibition

AU - Ding, Wen Xing

AU - Ni, Hong Min

AU - Yin, Xiao-Ming

PY - 2007/12

Y1 - 2007/12

N2 - 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.

AB - 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.

KW - ER stress

KW - MG132

KW - Non-apoptotic cell death

KW - Proteasome inhibitor

KW - Ubiquitin aggregates

KW - Vacuoles

UR - http://www.scopus.com/inward/record.url?scp=35948986297&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=35948986297&partnerID=8YFLogxK

U2 - 10.1007/s10495-007-0142-0

DO - 10.1007/s10495-007-0142-0

M3 - Article

VL - 12

SP - 2233

EP - 2244

JO - Apoptosis : an international journal on programmed cell death

JF - Apoptosis : an international journal on programmed cell death

SN - 1360-8185

IS - 12

ER -