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

Our plain-English summary of Loss of C/EBP-β LIP drives cisplatin resistance in malignant pleural mesothelioma, by J. Kopecka, I.C. Salaroglio, L. Righi, et al (Lung Cancer, 2018).

The study

• Authors: J. Kopecka, I.C. Salaroglio, L. Righi, R. Libener, S. Orecchia, F. Grosso, V. Milosevic, P. Ananthanarayanan, L. Ricci, E. Capelletto, M. Pradotto, F. Napoli, M. Di Maio, S. Novello, M. Rubinstein, G.V. Scagliotti, C. Riganti
• Journal: Lung Cancer
• Published: 2018;120:34-45
• Cited by: 32 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

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.

Copyright © 2018 Elsevier B.V. All rights reserved.

In plain English

This laboratory study did not examine asbestos exposure. It asked why malignant pleural mesothelioma resists the drug cisplatin. The authors used tumor cells from nine cisplatin-treated patients, normal mesothelial cells from three people without cancer, and mice. A protein called LIP, which promotes cell death under stress, was detectable only in the normal cells. In tumor cells it carried ubiquitin, a tag linked to breakdown, and more tagging went with greater cisplatin resistance in the lab. The five patients with the most tagging had median progression-free survival of 2.2 months and overall survival of 9 months, against 5.3 and 16 months for the other four. Restoring LIP made tumor cells more cisplatin-sensitive and slowed tumor growth in mice. The drugs carfilzomib and chloroquine blocked LIP breakdown. With cisplatin, they reduced tumor growth in mice, which showed no significant blood-count changes or signs of liver, kidney, heart or muscle toxicity. The authors called their patient data preliminary. With few patients and no comparison group given other treatments, they could not tell general prognosis apart from prediction of cisplatin response.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study using patient-derived mesothelioma cells and normal mesothelial cells, with a small survival comparison of the patients and experiments in mice
• Who was studied: Tumor samples from 9 patients with malignant pleural mesothelioma (3 epithelioid, 3 biphasic, 3 sarcomatous), obtained at diagnostic thoracoscopy. Comparison cells came from 3 patients with pleural fluid caused by congestive heart failure and no history of malignant disease. Ethics approval came from hospitals in Alessandria and Orbassano, Italy. A murine AB1 mesothelioma cell line was grown in female balb/C mice (10 per group). Study dates are not given.
• Exposure: No asbestos exposure was studied. The patients had received 5 cycles of cisplatin at 75 mg/m2 every 21 days. In the lab, the authors tested cisplatin, forced overexpression of LIP, the proteasome inhibitor carfilzomib and the lysosome inhibitor chloroquine, alone and in combination.
• Main results:
  • The LAP form of C/EBP-β protein was found in both normal mesothelial cells and mesothelioma cells. The LIP form was detectable only in the normal mesothelial cells.
  • In the 9 mesothelioma samples, the amount of ubiquitinated LIP was directly correlated with the dose of cisplatin needed to affect the cells in the lab (the IC50).
  • The 'LIP low' group was the 5 patients with the highest LIP ubiquitination. In this group, median progression-free survival was 2.2 months and median overall survival was 9 months after cisplatin therapy.
  • The 'LIP high' group was the 4 patients with the lowest LIP ubiquitination. In this group, median progression-free survival was 5.3 months and median overall survival was 16 months. The differences between groups were reported as p less than 0.03 for progression-free survival and p less than 0.01 for overall survival.
  • Mesothelioma cells engineered to overexpress LIP were more sensitive to cisplatin. They also activated the CHOP/TRB3/caspase 3 cell-death pathway.
  • In mice, AB1 tumors did not respond to cisplatin. Inducing LIP reduced tumor growth in both immune-deficient and immune-competent mice.
  • Compared with normal mesothelial cells, mesothelioma cells showed higher proteasome, autophagy and lysosome activity. Carfilzomib or chloroquine prevented LIP degradation.
  • Carfilzomib plus chloroquine reduced mesothelioma cell growth and tumor growth in mice, particularly when cisplatin was added. No significant blood-count changes and no signs of liver, kidney, heart or muscle toxicity were detected in mice given the triple combination.
• The authors' conclusion: The authors concluded that LIP levels strongly correlated with mesothelioma response to cisplatin in the lab. They described their data as preliminary and said it should be tested in larger patient groups. If confirmed, LIP ubiquitination might predict clinical response to cisplatin. They suggested that combinations of proteasome and lysosome inhibitors be included among the strategies being evaluated.
• Limitations the authors state:
  • The small number of patients, and the absence of a control group receiving different treatments, made it difficult to tell whether LIP ubiquitination reflects general prognosis or predicts response to cisplatin specifically.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Cisplatin, Pleural Mesothelioma, Chemotherapy, Phagocytosis, Apoptosis.

Related studies

• Interaction and cross-resistance of cisplatin and pemetrexed in malignant pleural mesothelioma cell lines — M. Kitazono-Saitoh, Y. Takiguchi, et al. (2012)
• Putative cancer stem cells in malignant pleural mesothelioma show resistance to cisplatin and pemetrexed — L. Cortes-Dericks, G.L. Carboni, et al. (2010)
• Prevalence of in vitro chemotherapeutic drug resistance in primary malignant pleural mesothelioma: result in a cohort of 203 resection specimens — A.A. Mujoomdar, T.R. Tilleman, et al. (2010)
• Nintedanib in combination with pemetrexed and cisplatin for chemotherapy-naive patients with advanced malignant pleural mesothelioma (LUME-Meso): a double-blind, randomised, placebo-controlled phase 3 trial — G.V. Scagliotti, R. Gaafar, et al. (2019)
• ERCC1, MLH1, MSH2, MSH6, and βIII-tubulin: resistance proteins associated with response and outcome to platinum-based chemotherapy in malignant pleural mesothelioma — S. Ting, F.D. Mairinger, et al. (2013)
• A phase II trial of prolonged, continuous infusion of low-dose gemcitabine plus cisplatin in patients with advanced malignant pleural mesothelioma — O. Arrieta, D. López-Macías, et al. (2014)

Browse more research in Lung Cancer, or return to medical research.