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Title: Gefitinib and Erlotinib Lead to Phosphorylation of Eukaryotic Initiation Factor 2 Alpha Independent of Epidermal Growth Factor Receptor in A549 Cells.
Authors: Koyama, Satoshi
Omura, Tomohiro  kyouindb  KAKEN_id
Yonezawa, Atsushi  kyouindb  KAKEN_id  orcid (unconfirmed)
Imai, Satoshi  kyouindb  KAKEN_id
Nakagawa, Shunsaku  kyouindb  KAKEN_id
Nakagawa, Takayuki  kyouindb  KAKEN_id
Yano, Ikuko
Matsubara, Kazuo
Author's alias: 大村, 友博
矢野, 育子
Issue Date: 19-Aug-2015
Publisher: Public Library of Science
Journal title: PLoS ONE
Volume: 10
Issue: 8
Thesis number: e0136176
Abstract: Gefitinib and erlotinib are anticancer agents, which inhibit epidermal growth factor receptor (EGFR) tyrosine kinase. Interstitial lung disease (ILD) occurs in patients with non-small cell lung cancer receiving EGFR inhibitors. In the present study, we examined whether gefitinib- and erlotinib-induced lung injury related to ILD through endoplasmic reticulum (ER) stress, which is a causative intracellular mechanism in cytotoxicity caused by various chemicals in adenocarcinomic human alveolar basal epithelial cells. These two EGFR inhibitors increased Parkinson juvenile disease protein 2 and C/EBP homologous protein mRNA expressions, and activated the eukaryotic initiation factor (eIF) 2α/activating transcription factor 4 pathway without protein kinase R-like ER kinase activation in A549 cells. Gefitinib and erlotinib caused neither ER stress nor cell death; however, these agents inhibited cell growth via the reduction of cyclin-D1 expression. Tauroursodeoxycholic acid, which is known to suppress eIF2α phosphorylation, cancelled the effects of EGFR inhibitors on cyclin-D1 expression and cell proliferation in a concentration-dependent manner. The results of an EGFR-silencing study using siRNA showed that gefitinib and erlotinib affected eIF2α phosphorylation and cyclin-D1 expression independent of EGFR inhibition. Therefore, the inhibition of cell growth by these EGFR inhibitors might equate to impairment of the alveolar epithelial cell repair system via eIF2α phosphorylation and reduced cyclin-D1 expression.
Rights: © 2015 Koyama et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI(Published Version): 10.1371/journal.pone.0136176
PubMed ID: 26288223
Appears in Collections:Journal Articles

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