Nicotine enhances hepatocyte growth factor-mediated lung cancer cell migration by activating the α7 nicotine acetylcholine receptor and phosphoinositide kinase-3-dependent pathway

Yoneyama,Remi; Aoshiba,Kazutetsu; Furukawa,Kinya; Saito,Makoto; Kataba,Hiroaki; Nakamura,Hiroyuki; Ikeda,Norihiko

doi:10.3892/ol.2015.3930

Nicotine enhances hepatocyte growth factor-mediated lung cancer cell migration by activating the α7 nicotine acetylcholine receptor and phosphoinositide kinase-3-dependent pathway

Authors:
- Remi Yoneyama
- Kazutetsu Aoshiba
- Kinya Furukawa
- Makoto Saito
- Hiroaki Kataba
- Hiroyuki Nakamura
- Norihiko Ikeda
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Affiliations: Department of Thoracic Surgery, Tokyo Medical University Hospital, Shinjuku‑ku, Tokyo 160‑0023, Japan, Department of Respiratory Medicine, Tokyo Medical University Ibaraki Medical Center, Inashiki‑gun, Ibaraki 300‑0395, Japan, Department of Chest Surgery, Tokyo Medical University Ibaraki Medical Center, Inashiki‑gun, Ibaraki 300‑0395, Japan
Published online on: November 17, 2015 https://doi.org/10.3892/ol.2015.3930
Pages: 673-677

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Abstract

Cigarette smoking not only promotes lung carcinogenesis, but it has also been demonstrated to promote the progression of lung cancer. Despite nicotine being a major component of cigarette smoke, it is not carcinogenic when acting alone. Instead, it is believed to function as a tumor promoter. Due to the fatal consequences of lung cancer being primarily associated with the processes of invasion and metastasis, the present study aimed to determine the effect of nicotine on the migratory activity of lung cancer cells. The effect of nicotine on the migration of lung cancer A549 cells was evaluated by a wound healing assay. Hepatocyte growth factor (HGF) was used as a pro‑migratory stimulus. During several of the experiments, specific inhibitors of α7‑nicotine acetylcholine receptor (α7‑nAchR), phosphoinositide kinase‑3 (PI3K) and extracellular signal‑related kinase (ERK)1/2 were included. The phosphorylation levels of Akt and ERK1/2 were examined using a cell‑based protein phosphorylation assay. It was observed that nicotine did not induce cell migration by itself, but that it instead promoted HGF‑induced cell migration. The effects of nicotine were inhibited by the pretreatment of the cells with the α7‑nAchR inhibitor, methyllycaconitine, and the PI3K inhibitor, LY294002. The mitogen‑activated protein kinase/ERK kinase kinase inhibitor exerted modest, but non‑significant inhibitory activity on the effect of nicotine. Nicotine did not induce Akt phosphorylation by itself, but instead promoted the HGF‑induced phosphorylation of Akt. It was also observed that nicotine had no effect on ERK1/2 phosphorylation. The results from the present study indicate that nicotine, when alone, does not have a pro‑migratory function, but instead enhances responsiveness to the pro‑migratory stimulus emitted by HGF. The current study provides an insight into the mechanism of tumor promotion by demonstrating that nicotine and α7‑nAchRs act in synergy with the HGF‑induced PI3K/Akt signaling pathway, increasing the sensitivity of lung cancer cells to HGF, and thereby promoting cell migration, a vital step in invasion and metastasis.

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