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.
Highlights
More than a million people in Taiwan consume betel nuts, and betel nut chewing is known as a risk factor for oral cancer and oral submucosal fibrosis, as described by the International Agency for Research on Cancer (IACR) [1,2,3]
We suggest that Arecoline consumption and activation of muscarinic acetylcholine receptor 3 (mAChR3) is positively correlated with lung cancer cell migration, and interrupting this potential pathway may lead to decreased lung cancer cell migration
We suggest that Arecoline activates the EGFR and c-Src/FAK signaling cascade to stimulate cell migration through regulation of mAChR3
Summary
More than a million people in Taiwan consume betel nuts, and betel nut chewing is known as a risk factor for oral cancer and oral submucosal fibrosis, as described by the International Agency for Research on Cancer (IACR) [1,2,3]. A tumorigenicity study in Swiss mice showed that betel nuts and betel quid induced lung cancer formation (47% and 26%, respectively) [6]. This data suggests that the habit of chewing betel nuts increases the risk of head and neck cancer, and elevates the systemic risk of carcinogenesis. Betel quid extract was found to promote cell migration in an esophageal squamous carcinoma cell line CE81T/VGH, and purified Arecoline treatment had a similar effect [11], while matrix metalloproteinase (MMP). Acetylcholine promoted lung cancer cell proliferation and migration through the mAChR3-activated EGFR/PI3K/Akt pathway accompanied by partial MMP activation [13,14,15]. We suggest that Arecoline consumption and activation of mAChR3 is positively correlated with lung cancer cell migration, and interrupting this potential pathway may lead to decreased lung cancer cell migration
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