Overcoming epithelial-mesenchymal transition-mediated drug resistance with monensin-based combined therapy in non-small cell lung cancer.
Antifungal Agents
/ pharmacology
Carcinoma, Non-Small-Cell Lung
/ drug therapy
Cell Survival
/ drug effects
Drug Repositioning
Drug Resistance, Neoplasm
/ drug effects
Epithelial-Mesenchymal Transition
/ drug effects
ErbB Receptors
/ antagonists & inhibitors
Humans
Lung Neoplasms
/ drug therapy
Monensin
/ pharmacology
Protein Kinase Inhibitors
/ pharmacology
Proton Ionophores
/ pharmacology
Transforming Growth Factor beta
/ metabolism
Drug repositioning
Drug resistance
Epithelial-mesenchymal transition
Monensin
Non-small cell lung cancer
Journal
Biochemical and biophysical research communications
ISSN: 1090-2104
Titre abrégé: Biochem Biophys Res Commun
Pays: United States
ID NLM: 0372516
Informations de publication
Date de publication:
27 08 2020
27 08 2020
Historique:
received:
10
06
2020
accepted:
17
06
2020
entrez:
2
8
2020
pubmed:
2
8
2020
medline:
13
2
2021
Statut:
ppublish
Résumé
The epithelial-mesenchymal transition (EMT) is a key process in tumor progression and metastasis and is also associated with drug resistance. Thus, controlling EMT status is a research of interest to conquer the malignant tumors. A drug repositioning analysis of transcriptomic data from a public cell line database identified monensin, a widely used in veterinary medicine, as a candidate EMT inhibitor that suppresses the conversion of the EMT phenotype. Using TGF-β-induced EMT cell line models, the effects of monensin on the EMT status and EMT-mediated drug resistance were assessed. TGF-β treatment induced EMT in non-small cell lung cancer (NSCLC) cell lines and the EGFR-mutant NSCLC cell lines with TGF-β-induced EMT acquired resistance to EGFR-tyrosine kinase inhibitor. The addition of monensin effectively suppressed the TGF-β-induced-EMT conversion, and restored the growth inhibition and the induction of apoptosis by the EGFR-tyrosine kinase inhibitor. Our data suggested that combined therapy with monensin might be a useful strategy for preventing EMT-mediated acquired drug resistance.
Sections du résumé
BACKGROUND
The epithelial-mesenchymal transition (EMT) is a key process in tumor progression and metastasis and is also associated with drug resistance. Thus, controlling EMT status is a research of interest to conquer the malignant tumors.
MATERIALS AND METHODS
A drug repositioning analysis of transcriptomic data from a public cell line database identified monensin, a widely used in veterinary medicine, as a candidate EMT inhibitor that suppresses the conversion of the EMT phenotype. Using TGF-β-induced EMT cell line models, the effects of monensin on the EMT status and EMT-mediated drug resistance were assessed.
RESULTS
TGF-β treatment induced EMT in non-small cell lung cancer (NSCLC) cell lines and the EGFR-mutant NSCLC cell lines with TGF-β-induced EMT acquired resistance to EGFR-tyrosine kinase inhibitor. The addition of monensin effectively suppressed the TGF-β-induced-EMT conversion, and restored the growth inhibition and the induction of apoptosis by the EGFR-tyrosine kinase inhibitor.
CONCLUSION
Our data suggested that combined therapy with monensin might be a useful strategy for preventing EMT-mediated acquired drug resistance.
Identifiants
pubmed: 32736704
pii: S0006-291X(20)31294-8
doi: 10.1016/j.bbrc.2020.06.077
pii:
doi:
Substances chimiques
Antifungal Agents
0
Protein Kinase Inhibitors
0
Proton Ionophores
0
Transforming Growth Factor beta
0
Monensin
906O0YJ6ZP
EGFR protein, human
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
760-765Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.