Abstract
BackgroundStandard 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.MethodsIn 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.ResultsMPM 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.ConclusionsWe 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.
Highlights
Malignant pleural mesothelioma (MPM) is a relatively rare but extremely aggressive cancer originating from transformation of mesothelial cells of the pleura
We showed that malignant pleural mesothelioma (MPM) cells resistant to first-line cisplatin/ mesothelioma (MPM) is a cisplatin/pemetrexed (MTA) chemotherapy display low basal level of endoplasmic reticulum (ER) stress and that bortezomib selectively impairs these cells by eliciting differential unfolded protein response (UPR), elevating the response to ER stress and augmenting apoptotic cell death
To test if 3D culture can be used to enrich chemotherapy-resistant population in MPM cells, we compared MPM cells propagated under 3D culture conditions and parental tumour cells grown in monolayer for their response to chemotherapy. 3D and 2D cells were treated with standard chemotherapeutic regimen and cell viability was determined 72 h after the treatment
Summary
Malignant pleural mesothelioma (MPM) is a relatively rare but extremely aggressive cancer originating from transformation of mesothelial cells of the pleura. No targeted therapies against MPM are available in the clinic, so current standard-of-care for patients with advanced MPM remains a dual chemotherapeutic regimen that combines cisplatin and pemetrexed (MTA).[5] Clinical evidence indicates that this therapeutic regimen elicits only modest efficacy,[6] rarely achieving durable clinical response because of drug resistance, de novo and/or acquired after initial therapeutic administration.[5, 7]. Standard treatment for advanced malignant pleural mesothelioma (MPM) is a cisplatin/pemetrexed (MTA) regimen; this is confronted by drug resistance. We hypothesise that ER stress and the adaptive unfolded protein response (UPR) play a role in chemotherapy resistance of MPM. 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
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