RRC ID 54115
Author Xu D, Liang SQ, Yang H, Lüthi U, Riether C, Berezowska S, Marti TM, Hall SRR, Bruggmann R, Kocher GJ, Schmid RA, Peng RW.
Title Increased sensitivity to apoptosis upon endoplasmic reticulum stress-induced activation of the unfolded protein response in chemotherapy-resistant malignant pleural mesothelioma.
Journal Br. J. Cancer
Abstract BACKGROUND:Standard treatment for advanced malignant pleural mesothelioma (MPM) is a cisplatin/pemetrexed (MTA) regimen; however, this is confronted by drug resistance. Proteotoxic stress in the endoplasmic reticulum (ER) is a hallmark of cancer and some rely on this stress signalling in response to cytotoxic chemotherapeutics. We hypothesise that ER stress and the adaptive unfolded protein response (UPR) play a role in chemotherapy resistance of MPM.
METHODS:In vitro three-dimensional (3D) and ex vivo organotypic culture were used to enrich a chemotherapy-resistant population and recapitulate an in vivo MPM microenvironment, respectively. Markers of ER stress, the UPR and apoptosis were assessed at mRNA and protein levels. Cell viability was determined based on acid phosphatase activity.
RESULTS:MPM cells with de novo and/or acquired chemotherapy resistance displayed low ER stress, which rendered the cells hypersensitive to agents that induce ER stress and alter the UPR. Bortezomib, an FDA-approved proteasome inhibitor, selectively impairs chemotherapy-resistant MPM cells by activating the PERK/eIF2α/ATF4-mediated UPR and augmenting apoptosis.
CONCLUSIONS:We provide the first evidence for ER stress and the adaptive UPR signalling in chemotherapy resistance of MPM, which suggests that perturbation of the UPR by altering ER stress is a novel strategy to treat chemotherapy-refractory MPM.
Volume 119(1)
Pages 65-75
Published 2018-7
DOI 10.1038/s41416-018-0145-3
PII 10.1038/s41416-018-0145-3
PMID 29921948
PMC PMC6035279
MeSH Activating Transcription Factor 4 / genetics Apoptosis / genetics Bortezomib / pharmacology* Cell Line, Tumor Drug Resistance, Neoplasm / genetics Endoplasmic Reticulum Endoplasmic Reticulum Stress / genetics Eukaryotic Initiation Factor-2 / genetics Gene Expression Regulation, Neoplastic / drug effects Humans Lung Neoplasms / drug therapy* Lung Neoplasms / genetics Lung Neoplasms / pathology Mesothelioma / drug therapy* Mesothelioma / genetics Mesothelioma / pathology Pleural Neoplasms / drug therapy* Pleural Neoplasms / genetics Pleural Neoplasms / pathology Signal Transduction / drug effects Unfolded Protein Response / drug effects Unfolded Protein Response / genetics* eIF-2 Kinase / genetics
IF 5.922
Resource
Human and Animal Cells ACC-MESO-1(RCB2292) ACC-MESO-4(RCB2293)