Nicotine promotes lymph node metastasis and cetuximab resistance in head and neck squamous cell carcinoma

Shimizu,Rieko; Ibaragi,Soichiro; Eguchi,Takanori; Kuwajima,Daisuke; Kodama,Shinichi; Nishioka,Takashi; Okui,Tatsuo; Obata,Kyoichi; Takabatake,Kiyofumi; Kawai,Hotaka; Ono,Kisho; Okamoto,Kuniaki; Nagatsuka,Hitoshi; Sasaki,Akira

doi:10.3892/ijo.2018.4631

Nicotine promotes lymph node metastasis and cetuximab resistance in head and neck squamous cell carcinoma

Authors:
- Rieko Shimizu
- Soichiro Ibaragi
- Takanori Eguchi
- Daisuke Kuwajima
- Shinichi Kodama
- Takashi Nishioka
- Tatsuo Okui
- Kyoichi Obata
- Kiyofumi Takabatake
- Hotaka Kawai
- Kisho Ono
- Kuniaki Okamoto
- Hitoshi Nagatsuka
- Akira Sasaki
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Affiliations: Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700‑8525, Japan, Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700‑8525, Japan, Department of Oral Diagnosis, Tohoku University Graduate School of Dentistry, Sendai 980‑8575, Japan, Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700‑8525, Japan, Department of Dental Pharmacology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700‑8525, Japan
Published online on: November 12, 2018 https://doi.org/10.3892/ijo.2018.4631
Pages: 283-294

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Abstract

Epidermal growth factor (EGF) is overexpressed in many cancers and is associated with worse prognosis. EGF binds to its cell surface receptor (EGFR), which induces EGFR phosphorylation. Phosphorylated EGFR (p‑EGFR) is translocated into the nucleus, which increases cancer cell activity. Nicotine, which is one of the main components of tobacco, is absorbed through pulmonary alveoli and mucosal epithelia in the head and neck region by smoking and moves into the blood. Nicotine in blood binds to nicotinic acetylcholine receptor (nAChR) in the central nervous system and serves a crucial role in tobacco addiction. Although nAChR localization is thought to be limited in the nervous system, nAChR is present in a wide variety of non‑neuronal cells, including cancer cells. Recent studies suggest that nicotine contributes to the metastasis and resistance to anti‑cancer drugs of various cancer cells. However, it remains unknown whether head and neck squamous cell carcinoma (HNSCC) cells can utilize nicotine‑nAChR signaling to metastasize and acquire resistance to anti‑cancer drugs, even though the mucosal epithelia of the head and neck region are the primary sites of exposure to tobacco smoke. To the best of our knowledge, the present study is the first to demonstrate the role of nicotine in metastasis and anti‑EGFR‑therapy resistance of HNSCC. The present findings demonstrated that nicotine increased proliferation, migration, invasion, p‑EGFR nuclear translocation and protein kinase B (Akt) phosphorylation in HNSCC cells. It was also demonstrated that nicotine restored cetuximab‑inhibited proliferation, migration and invasion of HNSCC cells. Finally, an in vivo experiment revealed that nicotine increased lymph node metastasis of xenografted tumors, whereas an nAChR inhibitor suppressed lymph node metastasis and p‑EGFR nuclear localization of xenografted tumors. Taken together, these results demonstrated that nicotine induced nuclear accumulation of p‑EGFR, and activation of Akt signaling. These signaling pathways elevated the activities of HNSCC cells, causing lymph node metastasis and serving a role in cetuximab resistance.

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