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Arecoline Promotes Migration of A549 Lung Cancer Cells through Activating the EGFR/Src/FAK Pathway

1
Department of Life Sciences, National Chung Hsing University, Taichung 40227, Taiwan
2
Medical Center for Exosomes and Mitochondria Related Diseases, China Medical University Hospital, Taichung 40447, Taiwan
3
Department of Nursing, Asia University, Taichung 41345, Taiwan
4
Department of Applied Chemistry, National Chi Nan University, Nantou 54561, Taiwan
5
Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
6
Division of Chest Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan
7
Division of Hematology/Medical Oncology, Taichung Veterans General Hospital, Taichung 40705, Taiwan
8
Division of Urology, Taichung Veterans General Hospital, Taichung 40705, Taiwan
9
Department of Nuclear Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan
10
Department of Surgery, Tung’s Taichung Metro Harbor Hospital, Taichung 435, Taiwan
11
Department of Microbiology and Immunology, Chang Gung Medical University, Taoyuan 33302, Taiwan
12
Department of Urology, University of Texas Southwestern Medical Center, TX 75390, USA
13
Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung 40227, Taiwan
14
Ph.D. Program in Translational Medicine and Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung 40227, Taiwan
*
Author to whom correspondence should be addressed.
These authors contributed equally to this paper.
Toxins 2019, 11(4), 185; https://doi.org/10.3390/toxins11040185
Received: 16 March 2019 / Revised: 25 March 2019 / Accepted: 26 March 2019 / Published: 28 March 2019
(This article belongs to the Special Issue Biological Activities of Alkaloids: From Toxicology to Pharmacology)
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Abstract

Arecoline is the primary alkaloid in betel nuts, which are known as a risk factor for oral submucosal fibrosis and oral cancer. Lung cancer is a severe type of carcinoma with high cell motility that is difficult to treat. However, the detailed mechanisms of the correlation between Arecoline and lung cancer are not fully understood. Here, we investigated the effect of Arecoline on migration in lung cancer cell lines and its potential mechanism through the muscarinic acetylcholine receptor 3 (mAChR3)-triggered EGFR/Src/FAK pathway. Our results indicate that different concentrations of Arecoline treatment (10 µM, 20 µM, and 40 µM) significantly increased the cell migration ability in A549 and CL1-0 cells and promoted the formation of the filamentous actin (F-actin) cytoskeleton, which is a crucial element for cell migration. However, migration of H460, CL1-5, and H520 cell lines, which have a higher migration ability, was not affected by Arecoline treatment. The EGFR/c-Src/Fak pathway, which is responsible for cell migration, was activated by Arecoline treatment, and a decreased expression level of E-cadherin, which is an epithelial marker, was observed in Arecoline-treated cell lines. Blockade of the EGFR/c-Src/Fak pathway with the inhibitors of EGFR (Gefitinib) or c-Src (Dasatinib) significantly prevented Arecoline-promoted migration in A549 cells. Gefitinib or Dasatinib treatment significantly disrupted the Arecoline-induced localization of phospho-Y576-Fak during focal adhesion in A549 cells. Interestingly, Arecoline-promoted migration in A549 cells was blocked by a specific mAChR3 inhibitor (4-DAMP) or a neutralizing antibody of matrix metalloproteinase (MMP7 or Matrilysin). Taken together, our findings suggest that mAChR3 might play an essential role in Arecoline-promoted EGFR/c-Src/Fak activation and migration in an A549 lung cancer cell line. View Full-Text
Keywords: Arecoline; lung cancer cells; mAchR3; EGFR; SRC; FAK Arecoline; lung cancer cells; mAchR3; EGFR; SRC; FAK
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Chang, C.-H.; Chen, M.-C.; Chiu, T.-H.; Li, Y.-H.; Yu, W.-C.; Liao, W.-L.; Oner, M.; Yu, C.-T.R.; Wu, C.-C.; Yang, T.-Y.; Teng, C.-L.J.; Chiu, K.-Y.; Chen, K.-C.; Wang, H.-Y.; Yue, C.-H.; Lai, C.-H.; Hsieh, J.-T.; Lin, H. Arecoline Promotes Migration of A549 Lung Cancer Cells through Activating the EGFR/Src/FAK Pathway. Toxins 2019, 11, 185.

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