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

Lung Cancer : Journal of the International Association for the Study of Lung Cancer
Joanna KopeckaChiara Riganti

Abstract

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...Continue Reading

Citations

Mar 27, 2020·Journal for Immunotherapy of Cancer·Lorenzo GalluzziFrancesco M Marincola
Jan 20, 2019·Proceedings of the National Academy of Sciences of the United States of America·Tania VillanovaRiccarda Granata
Nov 30, 2018·Journal of Experimental & Clinical Cancer Research : CR·Iris C SalaroglioJoanna Kopecka
May 21, 2019·International Journal of Cancer. Journal International Du Cancer·Vladan MilosevicChiara Riganti
Sep 8, 2019·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Teodora Alexa-StratulatChiara Riganti
Mar 12, 2021·Thorax·Marie ShamseddinStefan John Marciniak
Feb 7, 2021·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Kathrin OehlPeter J Wild

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