Lung cancer (Amsterdam, Netherlands) · 2018
Loss of C/EBP-β LIP drives cisplatin resistance in malignant pleural mesothelioma.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Kopecka Joanna, Salaroglio Iris C, Righi Luisella, Libener Roberta, Orecchia Sara, Grosso Federica, Milosevic Vladan, Ananthanarayanan Preeta, Ricci Luisa, Capelletto Enrica, Pradotto Monica, Napoli Francesca, Di Maio Massimo, Novello Silvia, Rubinstein Menachem, Scagliotti Giorgio V, Riganti Chiara
Аннотация
OBJECTIVES: Cisplatin-based chemotherapy is moderately active in malignant pleural mesothelioma (MPM) due to intrinsic drug resistance and to low immunogenicity of MPM cells. CAAT/enhancer binding protein (C/EBP)-β LIP is a pro-apoptotic and chemosensitizing transcription factor activated in response to endoplasmic reticulum (ER) stress.
MATERIALS AND METHODS: We investigated if LIP levels can predict the clinical response to cisplatin and survival of MPM patients receiving cisplatin-based chemotherapy. We studied the LIP-dependent mechanisms determining cisplatin-resistance and we identified pharmacological approaches targeting LIP, able to restore cisplatin sensitiveness, in patient-derived MPM cells and animal models. Results were analyzed by a one-way analysis of variance test.
RESULTS: We found that LIP was degraded by constitutive ubiquitination in primary MPM cells derived from patients poorly responsive to cisplatin. LIP ubiquitination was directly correlated with cisplatin chemosensitivity and was associated with patients' survival after chemotherapy. Overexpression of LIP restored cisplatin's pro-apoptotic effect by activating CHOP/TRB3/caspase 3 axis and up-regulating calreticulin, that triggered MPM cell phagocytosis by dendritic cells and expanded autologous anti-tumor CD8+CD107+T-cytotoxic lymphocytes. Proteasome inhibitor carfilzomib and lysosome inhibitor chloroquine prevented LIP degradation. The triple combination of carfilzomib, chloroquine and cisplatin increased ER stress-triggered apoptosis and immunogenic cell death in patients' samples, and reduced tumor growth in cisplatin-resistant MPM preclinical models.
CONCLUSION: The loss of LIP mediates cisplatin resistance, rendering LIP a possible predictor of cisplatin response in MPM patients. The association of proteasome and lysosome inhibitors reverses cisplatin resistance by restoring LIP levels and may represent a new adjuvant strategy in MPM treatment.
MATERIALS AND METHODS: We investigated if LIP levels can predict the clinical response to cisplatin and survival of MPM patients receiving cisplatin-based chemotherapy. We studied the LIP-dependent mechanisms determining cisplatin-resistance and we identified pharmacological approaches targeting LIP, able to restore cisplatin sensitiveness, in patient-derived MPM cells and animal models. Results were analyzed by a one-way analysis of variance test.
RESULTS: We found that LIP was degraded by constitutive ubiquitination in primary MPM cells derived from patients poorly responsive to cisplatin. LIP ubiquitination was directly correlated with cisplatin chemosensitivity and was associated with patients' survival after chemotherapy. Overexpression of LIP restored cisplatin's pro-apoptotic effect by activating CHOP/TRB3/caspase 3 axis and up-regulating calreticulin, that triggered MPM cell phagocytosis by dendritic cells and expanded autologous anti-tumor CD8+CD107+T-cytotoxic lymphocytes. Proteasome inhibitor carfilzomib and lysosome inhibitor chloroquine prevented LIP degradation. The triple combination of carfilzomib, chloroquine and cisplatin increased ER stress-triggered apoptosis and immunogenic cell death in patients' samples, and reduced tumor growth in cisplatin-resistant MPM preclinical models.
CONCLUSION: The loss of LIP mediates cisplatin resistance, rendering LIP a possible predictor of cisplatin response in MPM patients. The association of proteasome and lysosome inhibitors reverses cisplatin resistance by restoring LIP levels and may represent a new adjuvant strategy in MPM treatment.
Предметные рубрики MeSH
Adaptor Proteins, Signal TransducingAntineoplastic AgentsApoptosisCCAAT-Enhancer-Binding Protein-betaCD8-Positive T-LymphocytesCisplatinDendritic CellsDrug Resistance, NeoplasmHumansLung NeoplasmsLymphocyte ActivationMesotheliomaMesothelioma, MalignantOligopeptidesPleural NeoplasmsPrognosisProteolysisSurvival AnalysisTumor Cells, CulturedUbiquitination