RRC ID 54730
Author Shimizu R, Ibaragi S, Eguchi T, Kuwajima D, Kodama S, Nishioka T, Okui T, Obata K, Takabatake K, Kawai H, Ono K, Okamoto K, Nagatsuka H, Sasaki A.
Title Nicotine promotes lymph node metastasis and cetuximab resistance in head and neck squamous cell carcinoma.
Journal Int J Oncol
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.
Volume 54(1)
Pages 283-294
Published 2019-1
DOI 10.3892/ijo.2018.4631
PMID 30431077
MeSH Animals Cell Line, Tumor Cell Movement Cell Nucleus / metabolism Cell Proliferation Cell Survival Cetuximab / pharmacology* Drug Resistance, Neoplasm* ErbB Receptors / metabolism Head and Neck Neoplasms / drug therapy Head and Neck Neoplasms / metabolism* Humans Lymphatic Metastasis Mice Nicotine / adverse effects* Phosphorylation Protein Transport / drug effects Proto-Oncogene Proteins c-akt / metabolism Receptors, Nicotinic / metabolism Signal Transduction / drug effects Squamous Cell Carcinoma of Head and Neck / drug therapy Squamous Cell Carcinoma of Head and Neck / metabolism* TOR Serine-Threonine Kinases / metabolism
IF 3.571
Times Cited 5
Human and Animal Cells HSC-2(RCB1945) HSC-3(RCB1975)