Loss of C/EBP-β LIP drives cisplatin resistance in malignant pleural mesothelioma

• Published in: Lung cancer (Amsterdam, Netherlands) Vol. 120; pp. 34 - 45
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.06.2018
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Antineoplastic Agents - therapeutic use; Apoptosis; CAAT/enhancer binding protein; CCAAT-Enhancer-Binding Protein-beta - genetics; CCAAT-Enhancer-Binding Protein-beta - metabolism; CD8-Positive T-Lymphocytes - immunology; Cisplatin - therapeutic use; Cisplatin resistance; Dendritic Cells - immunology; Drug Resistance, Neoplasm - genetics; Endoplasmic reticulum stress; Humans; Immunogenic cell death; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - mortality; Lymphocyte Activation; Malignant pleural mesothelioma; Mesothelioma - drug therapy; Mesothelioma - genetics; Mesothelioma - mortality; Mesothelioma, Malignant; Oligopeptides - pharmacology; Pleural Neoplasms - drug therapy; Pleural Neoplasms - mortality; Prognosis; Proteolysis; Survival Analysis; Tumor Cells, Cultured; Ubiquitination; C/EBP; TRB3; MPM; ChIP; Endoplasmic reticulum stress; UPN; ANOVA; IRE1; EMA; SPSS; PFS; CAAT/enhancer binding protein; CEA; Immunogenic cell death; HMC; OS; TBS; qRT-PCR; EIF2AK3/PERK; ICD; ER; WT1; CHOP/GADD153; Malignant pleural mesothelioma; Cisplatin resistance; ATF6; DC
• ISSN: 0169-5002; 1872-8332
• DOI: 10.1016/j.lungcan.2018.03.022

•C/EBP-β LIP loss correlates with poor response to cisplatin in mesothelioma patients.•C/EBP-β LIP loss is due to its constitutive ubiquitination and degradation.•Lack of C/EBP-β LIP prevents cisplatin-induced apoptosis and immunogenic cell death.•Proteasome and lysosome inhibitors restoring C/EBP-β LIP rescue cisplatin efficacy. 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. 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. 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. 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.