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Erlotinib inhibits epithelial mesenchymal transition of cigarette smoke‐exposed human retinal pigment epithelial cells through regulation of the FAK‐Syk/Src pathway
Author(s) -
PARK GABIN,
KIM DAEJIN
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.667.5
Subject(s) - epithelial–mesenchymal transition , microbiology and biotechnology , signal transduction , proto oncogene tyrosine protein kinase src , erlotinib , focal adhesion , cancer research , chemistry , vimentin , mesenchymal stem cell , tyrosine kinase , tyrosine phosphorylation , phosphorylation , epidermal growth factor receptor , biology , receptor , downregulation and upregulation , immunology , biochemistry , immunohistochemistry , gene
Cigarette smoke (CS)‐induced oxidative stress modifies the characteristics of retina pigmental epithelial (RPE) cells to express growth factors, including epidermal growth factor (EGF). Stimulation of lung cancer cells with CS activates aberrant downstream signaling pathways of EGF receptor (EGFR). However, the molecular mechanism of epithelial‐mesenchymal transition (EMT) processes in RPE cells stimulated by cigarette smoke extract (CSE) remains largely unknown. In this study, we focused on the underlying signaling pathways to identify the key molecules that are involved in EMT of CSE‐exposed RPE cells. Cultured human ARPE‐19 cells were cultured in the presence of 5% CSE for 4 weeks. Expression and activation of mesenchymal markers and EMT‐related signaling pathways (FAK, Src family, and Smad2/3) were determined by immunoblot analysis. Secretion of VEGF, IL‐6, IL‐8, and TGF‐β1 were investigated by ELISA assay. CSE‐induced migration was measured by wound healing assay. Exposure to CSE of RPE cells induced the secretion of VEGF, IL‐6, IL‐8, and TGF‐β1 as well as the expression of vimentin and α‐SMA. CSE‐mediated Syk/Src activation resulted in the phosphorylation of focal adhesion kinase (FAK), leading to migration and invasion of RPE cells. Pharmacological inhibition of Syk/Src or gene silencing of FAK with siRNA prevented the CSE‐mediated VEGF and TGF‐β1 production and blocked the phosphorylation of Smad2/3 in CSE‐stimulated RPE cells. Erlotinib, an EGF receptor tyrosine kinase inhibitor, profoundly attenuated the level of mesenchymal phenotypes in EGF and CSE‐treated RPE cells. Our results provide new concepts about EGF‐like role of CSE against RPE cells and suggest a possible new therapeutic target and measure for proliferative retinopathy (PVR). Support or Funding Information The present study was supported by the Basic Science Research Program of the Ministry of Education (grant no. NRF‐2015R1D1A1A01056672) and Ministry of Science, ICT & Future Planning (grant no. NRF‐2015R1C1A2A01053732) through the National Research Foundation (NRF) of the Republic of Korea. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .