Exposure to nicotine-derived nitrosamine ketone and arecoline synergistically facilitates tumor aggressiveness via overexpression of epidermal growth factor receptor and its downstream signaling in head and neck squamous cell carcinoma

• Published in: PloS one Vol. 13; no. 8; p. e0201267
• Main Authors: Yang, Shih-Hsien, Lee, Tsai-Yu, Ho, Chun An, Yang, Chin-Yuh, Huang, Wen-Yen, Lin, Yu-Chun, Nieh, Shin, Lin, Yaoh-Shiang, Chen, Su-Feng, Lin, Fu-Huang
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 27.08.2018; Public Library of Science (PLoS)
• Subjects: 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone; AKT protein; Apoptosis; Biology and Life Sciences; Cancer; Cancer therapies; Carcinogenesis; Carcinogens; Care and treatment; Cell cycle; Cell growth; Cisplatin; Combined treatment; Comparative analysis; Cytotoxicity; Dentistry; Development and progression; Diagnosis; Epidermal growth factor; Epidermal growth factor receptors; Exposure; Growth factors; Head & neck cancer; Head and neck cancer; Health aspects; Hospitals; Ketones; Kinases; Larynx; Medical prognosis; Medical research; Medicine and Health Sciences; Metastasis; Molecular modelling; NF-κB protein; Nicotine; Nitrosamine; Otolaryngology; Pathology; Pharmaceutical sciences; Physical Sciences; Promotion; Research and Analysis Methods; Signaling; Smoking; Squamous cell carcinoma; Squamous cell tumors; Stem cells; Surgery; Synergistic effect; Tobacco; Tumors; Taiwan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0201267

Long-term nicotine-derived nitrosamine ketone (NNK) and arecoline exposure promotes carcinogenesis and head and neck squamous cell carcinoma (HNSCC) progression, although most associated data on the two were analyzed individually. The molecular mechanisms underlying tumor progression associated with the synergistic effects of NNK and arecoline remain unclear. We treated SCC-25 and FaDu cells with NNK and arecoline (separately or in combination) for 3 months. Comparative analysis was performed to investigate the mechanism underlying the acquisition of properties related to tumor promotion, including stemness, anti-apoptosis, and resistance to HNSCC therapeutics. Long-term exposure to NNK and arecoline resulted in an increase in cancer stem cell properties, anti-apoptosis, and the resistance to cisplatin in HNSCC. We detected abundant epidermal growth factor receptor (EGFR) expression in HNSCC cells after combined treatment with NNK and arecoline. EGFR was pivotal in inducing tumor promotion and anti-apoptosis in cancer cells by inducing pAKT and NFκB. Combined treatment with NNK and arecoline synergistically facilitated tumor aggressiveness via EGFR-AKT signaling. Targeting EGFR-AKT signaling may be a feasible strategy for treating HNSCC.