Nintedanib inhibits epithelial-mesenchymal transition in A549 alveolar epithelial cells through regulation of the TGF-β/Smad pathway.

A549 Cells Epithelial Cells / metabolism Epithelial-Mesenchymal Transition / drug effects Gene Expression / drug effects Humans Indoles / pharmacology Phosphorylation / drug effects Pulmonary Alveoli / cytology Signal Transduction / drug effects Smad2 Protein / metabolism Transforming Growth Factor beta2 / metabolism Tumor Necrosis Factor-alpha / pharmacology
Epithelial-mesenchymal transition Microarray Nintedanib Pulmonary fibrosis Smad

Journal

Respiratory investigation
ISSN: 2212-5353
Titre abrégé: Respir Investig
Pays: Netherlands
ID NLM: 101581124

Informations de publication

Date de publication:
Jul 2020
Historique:
received: 03 08 2019
revised: 07 01 2020
accepted: 21 01 2020
pubmed: 4 5 2020
medline: 18 9 2020
entrez: 4 5 2020
Statut: ppublish

Résumé

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disorder. Recent studies have suggested that epithelial-mesenchymal transition (EMT) of alveolar epithelial cells influences development of pulmonary fibrosis, which is mediated by transforming growth factor β (TGF-β). Tumor necrosis factor α (TNF-α), an important proinflammatory cytokine in IPF, has been shown to enhance TGF-β-induced EMT. Nintedanib, a multiple tyrosine kinase inhibitor that is currently used to treat IPF, has been shown to suppress EMT in various cancer cell lines. However, the mechanism of EMT inhibition by nintedanib and its effect on TGF-β and TNF-α signaling pathways in alveolar epithelial cells have not been fully elucidated. A549 alveolar epithelial cells were stimulated with TGF-β2 and TNF-α, and the effects of nintedanib on global gene expression were evaluated using microarray analysis. Furthermore, Smad2/3 phosphorylation was assessed using western blotting. We found that in A549 cells, TGF-β2 and TNF-α treatment induces EMT, which was inhibited by nintedanib. Gene ontology analysis showed that nintedanib significantly attenuates the gene expression of EMT-related cellular pathways and the TGF-β signaling pathway, but not in the TNF-α-mediated signaling pathway. Furthermore, hierarchical cluster analysis revealed that EMT-related genes were attenuated in nintedanib-treated cells. Additionally, nintedanib was found to markedly suppress phosphorylation of Smad2/3. Nintedanib inhibits EMT by mediating EMT-related gene expression and the TGF-β/Smad pathway in A549 alveolar epithelial cells.

Sections du résumé

BACKGROUND BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disorder. Recent studies have suggested that epithelial-mesenchymal transition (EMT) of alveolar epithelial cells influences development of pulmonary fibrosis, which is mediated by transforming growth factor β (TGF-β). Tumor necrosis factor α (TNF-α), an important proinflammatory cytokine in IPF, has been shown to enhance TGF-β-induced EMT. Nintedanib, a multiple tyrosine kinase inhibitor that is currently used to treat IPF, has been shown to suppress EMT in various cancer cell lines. However, the mechanism of EMT inhibition by nintedanib and its effect on TGF-β and TNF-α signaling pathways in alveolar epithelial cells have not been fully elucidated.
METHODS METHODS
A549 alveolar epithelial cells were stimulated with TGF-β2 and TNF-α, and the effects of nintedanib on global gene expression were evaluated using microarray analysis. Furthermore, Smad2/3 phosphorylation was assessed using western blotting.
RESULTS RESULTS
We found that in A549 cells, TGF-β2 and TNF-α treatment induces EMT, which was inhibited by nintedanib. Gene ontology analysis showed that nintedanib significantly attenuates the gene expression of EMT-related cellular pathways and the TGF-β signaling pathway, but not in the TNF-α-mediated signaling pathway. Furthermore, hierarchical cluster analysis revealed that EMT-related genes were attenuated in nintedanib-treated cells. Additionally, nintedanib was found to markedly suppress phosphorylation of Smad2/3.
CONCLUSION CONCLUSIONS
Nintedanib inhibits EMT by mediating EMT-related gene expression and the TGF-β/Smad pathway in A549 alveolar epithelial cells.

Identifiants

DOI: 10.1016/j.resinv.2020.01.003 PMID: 32359980
pubmed: 32359980
pii: S2212-5345(20)30008-3
doi: 10.1016/j.resinv.2020.01.003
pii:
doi:

Substances chimiques

Indoles 0
SMAD2 protein, human 0
Smad2 Protein 0
Transforming Growth Factor beta2 0
Tumor Necrosis Factor-alpha 0
nintedanib G6HRD2P839

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

275-284

Informations de copyright

Copyright © 2020 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Competing Interest Kazuhisa Takahashi (K.T.) received research funding from Chugai Pharm, Ono Pharma, Taiho Pharm, Nippon Boehringer Ingelheim, AstraZeneca, Pfizer, MSD, and Lilly Japan. Motoyasu Kato (M.K.) received speaker honoraria from Nippon Boehringer Ingelheim. The remaining authors declare no conflict of interest.

Auteurs

Hiroaki Ihara (H)

Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University, Graduate School of Medicine, Tokyo, Japan. Electronic address: h-ihara@juntendo.ac.jp.

Yoichiro Mitsuishi (Y)

Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University, Graduate School of Medicine, Tokyo, Japan.

Motoyasu Kato (M)

Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University, Graduate School of Medicine, Tokyo, Japan.

Fumiyuki Takahashi (F)

Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University, Graduate School of Medicine, Tokyo, Japan.

Ken Tajima (K)

Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University, Graduate School of Medicine, Tokyo, Japan.

Takuo Hayashi (T)

Department of Human Pathology, Juntendo University, Graduate School of Medicine, Tokyo, Japan.

Moulid Hidayat (M)

Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University, Graduate School of Medicine, Tokyo, Japan.

Wira Winardi (W)

Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University, Graduate School of Medicine, Tokyo, Japan.

Aditya Wirawan (A)

Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University, Graduate School of Medicine, Tokyo, Japan.

Daisuke Hayakawa (D)

Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University, Graduate School of Medicine, Tokyo, Japan.

Koichiro Kanamori (K)

Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University, Graduate School of Medicine, Tokyo, Japan.

Naohisa Matsumoto (N)

Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University, Graduate School of Medicine, Tokyo, Japan.

Toshifumi Yae (T)

Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University, Graduate School of Medicine, Tokyo, Japan.

Tadashi Sato (T)

Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University, Graduate School of Medicine, Tokyo, Japan.

Shinichi Sasaki (S)

Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University, Graduate School of Medicine, Tokyo, Japan.

Kazuya Takamochi (K)

Department of General Thoracic Surgery,Juntendo University, Graduate School of Medicine, Tokyo, Japan.

Yoshiyuki Suehara (Y)

Department of Orthopedic Surgery, Juntendo University, Graduate School of Medicine, Tokyo, Japan.

Dai Ogura (D)

Link Genomics, Incorporated, Tokyo, Japan.

Shin-Ichiro Niwa (SI)

Link Genomics, Incorporated, Tokyo, Japan.

Kenji Suzuki (K)

Department of General Thoracic Surgery,Juntendo University, Graduate School of Medicine, Tokyo, Japan.

Kazuhisa Takahashi (K)

Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University, Graduate School of Medicine, Tokyo, Japan.

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Classifications MeSH

questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules A549 › Nintedanib inhibits epithelial-mesenchymal...
questionsmedicales.fr › Cellules › Cellules épithéliales › Nintedanib inhibits epithelial-mesenchymal...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transdifférenciation cellulaire › Transition épithélio-mésenchymateuse › Nintedanib inhibits epithelial-mesenchymal...
questionsmedicales.fr › Phénomènes génétiques › Expression des gènes › Nintedanib inhibits epithelial-mesenchymal...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Nintedanib inhibits epithelial-mesenchymal...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Indoles › Nintedanib inhibits epithelial-mesenchymal...
questionsmedicales.fr › Métabolisme › Phosphorylation › Nintedanib inhibits epithelial-mesenchymal...
questionsmedicales.fr › Appareil respiratoire › Poumon › Alvéoles pulmonaires › Nintedanib inhibits epithelial-mesenchymal...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Nintedanib inhibits epithelial-mesenchymal...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Protéines Smad › Protéines Smad régulées par les récepteurs › Protéine Smad2 › Nintedanib inhibits epithelial-mesenchymal...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Protéines de la superfamille du TGF bêta › Facteur de croissance transformant bêta › Facteur de croissance transformant bêta-2 › Nintedanib inhibits epithelial-mesenchymal...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Facteurs de nécrose tumorale › Facteur de nécrose tumorale alpha › Nintedanib inhibits epithelial-mesenchymal...