Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
Department of Medical Administration Office, National Defense Medical Center & Tri-Service General Hospital Beitou Branch, Taipei, Taiwan.
PLoS One. 2018 Aug 27;13(8):e0201267. doi: 10.1371/journal.pone.0201267. eCollection 2018.
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.
长期接触尼古丁衍生的亚硝胺酮（NNK）和槟榔碱会促进致癌作用和头颈部鳞状细胞癌（HNSCC）的进展，尽管大多数相关数据都是单独分析的。NNK 和槟榔碱协同作用导致肿瘤进展的分子机制尚不清楚。我们用 NNK 和槟榔碱（单独或联合）处理 SCC-25 和 FaDu 细胞 3 个月。进行了对比分析，以研究与肿瘤促进相关特性获得的机制，包括干性、抗凋亡和对 HNSCC 治疗的耐药性。长期暴露于 NNK 和槟榔碱导致 HNSCC 中癌症干细胞特性增加、抗凋亡和对顺铂的耐药性增加。我们在 NNK 和槟榔碱联合处理后检测到 HNSCC 细胞中表皮生长因子受体（EGFR）的大量表达。EGFR 通过诱导 pAKT 和 NFκB，在诱导癌细胞的肿瘤促进和抗凋亡中起关键作用。NNK 和槟榔碱联合处理通过 EGFR-AKT 信号协同促进肿瘤侵袭性。靶向 EGFR-AKT 信号可能是治疗 HNSCC 的一种可行策略。
