Elevation of proteasomal substrate levels sensitizes cells to apoptosis induced by inhibition of proteasomal deubiquitinases

Inhibitors of the catalytic activity of the 20S proteasome are cytotoxic to tumor cells and are currently in clinical use for treatment of multiple myeloma, whilst the deubiquitinase activity associated with the 19S regulatory subunit of the proteasome is also a valid target for anti-cancer drugs. T...

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Published in:PloS one 2014, Vol.9 (10), p.e108839-e108839
Main Authors: Sun, Chao, Roboti, Peristera, Puumalainen, Marjo-Riitta, Fryknäs, Mårten, Wang, Xin, D'Arcy, Padraig, Hult, Malin, High, Stephen, Linder, Stig, Swanton, Eileithyia
Format: Article
Language:English
Subjects:
Amino acids
Apoptosis
Biology and Life Sciences
Cancer
Catalysis
Catalytic activity
Cell death
Chemotherapy
Cysteine - metabolism
Cysteine - pharmacology
Cytoprotection - drug effects
Cytotoxicity
Drugs
Endoplasmic reticulum
Endoplasmic Reticulum - drug effects
Endoplasmic Reticulum - metabolism
HCT116 Cells
Heat shock proteins
HeLa Cells
Homeostasis
Humans
Hypotheses
Inhibitors
Life sciences
Medicin och hälsovetenskap
Medicine and Health Sciences
Molecular Weight
Multiple myeloma
Neurodegeneration
Oncology
Pathology
Piperidones - pharmacology
Polypeptides
Polyubiquitin - metabolism
Proteasome Endopeptidase Complex - metabolism
Proteasome Inhibitors - pharmacology
Proteasomes
Protein transport
Protein Transport - drug effects
Proteolysis - drug effects
Saposins - metabolism
Substrate inhibition
Substrate Specificity - drug effects
Substrates
Toxicity
Translocation
Tumor cell lines
Tumor cells
Ubiquitin
Ubiquitin-Specific Proteases - antagonists & inhibitors
Ubiquitin-Specific Proteases - metabolism
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cited_by cdi_FETCH-LOGICAL-c651t-2138529b7226743b9eb2123572b725af70d532655453e21acd8c1237bf85cb203
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creator Sun, Chao
Roboti, Peristera
Puumalainen, Marjo-Riitta
Fryknäs, Mårten
Wang, Xin
D'Arcy, Padraig
Hult, Malin
High, Stephen
Linder, Stig
Swanton, Eileithyia
description Inhibitors of the catalytic activity of the 20S proteasome are cytotoxic to tumor cells and are currently in clinical use for treatment of multiple myeloma, whilst the deubiquitinase activity associated with the 19S regulatory subunit of the proteasome is also a valid target for anti-cancer drugs. The mechanisms underlying the therapeutic efficacy of these drugs and their selective toxicity towards cancer cells are not known. Here, we show that increasing the cellular levels of proteasome substrates using an inhibitor of Sec61-mediated protein translocation significantly increases the extent of apoptosis that is induced by inhibition of proteasomal deubiquitinase activity in both cancer derived and non-transformed cell lines. Our results suggest that increased generation of misfolded proteasome substrates may contribute to the mechanism(s) underlying the increased sensitivity of tumor cells to inhibitors of the ubiquitin-proteasome system.
doi_str_mv 10.1371/journal.pone.0108839
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subjects Amino acids
Apoptosis
Biology and Life Sciences
Cancer
Catalysis
Catalytic activity
Cell death
Chemotherapy
Cysteine - metabolism
Cysteine - pharmacology
Cytoprotection - drug effects
Cytotoxicity
Drugs
Endoplasmic reticulum
Endoplasmic Reticulum - drug effects
Endoplasmic Reticulum - metabolism
HCT116 Cells
Heat shock proteins
HeLa Cells
Homeostasis
Humans
Hypotheses
Inhibitors
Life sciences
Medicin och hälsovetenskap
Medicine and Health Sciences
Molecular Weight
Multiple myeloma
Neurodegeneration
Oncology
Pathology
Piperidones - pharmacology
Polypeptides
Polyubiquitin - metabolism
Proteasome Endopeptidase Complex - metabolism
Proteasome Inhibitors - pharmacology
Proteasomes
Protein transport
Protein Transport - drug effects
Proteolysis - drug effects
Saposins - metabolism
Substrate inhibition
Substrate Specificity - drug effects
Substrates
Toxicity
Translocation
Tumor cell lines
Tumor cells
Ubiquitin
Ubiquitin-Specific Proteases - antagonists & inhibitors
Ubiquitin-Specific Proteases - metabolism
title Elevation of proteasomal substrate levels sensitizes cells to apoptosis induced by inhibition of proteasomal deubiquitinases
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