Nicotine Induces Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor by 1 Nicotinic Acetylcholine Receptor–Mediated Activation in PC9 Cells
Nicotine Induces Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor by 1 Nicotinic Acetylcholine Receptor–Mediated Activation in PC9 Cells
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DOI：
10.1097/jto.0b013e31828b51d4
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发表时间：
2013-06
影响因子：
20.4
通讯作者：
Shuo Wang;K. Takayama;Kentaro Tanaka;M. Takeshita;Noriaki Nakagaki;Kayo Ijichi;Heyan Li;Y. Nakanishi
中科院分区：
文献类型：
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作者：
Shuo Wang;K. Takayama;Kentaro Tanaka;M. Takeshita;Noriaki Nakagaki;Kayo Ijichi;Heyan Li;Y. Nakanishi
简介：尼古丁是香烟烟雾中4000种已识别化学物质中的主要成分，它与非小细胞肺癌（NSCLC）细胞上的尼古丁乙酰胆碱受体（nAChR）结合，并通过激活有丝分裂原活化蛋白激酶来调节细胞增殖[AQ：MAPK]已扩展到有丝分裂原活化蛋白激酶。请批准）。和PI 3 K/Akt通路。在持续吸烟的吸烟相关肺癌患者中，表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）的抗癌作用弱于非吸烟者;然而，这种差异的确切原因尚不清楚。我们研究了1 nAChR亚基在这种现象中的作用。方法：对3种NSCLC细胞系进行1 nAChR mRNA的筛选，并对切除的原发性NSCLC组织进行蛋白质分析。我们使用Western blot和RNA干扰（siRNA）方法来证实结果。结果：我们确定1 nAChR在尼古丁诱导的细胞信号传导和尼古丁诱导的EGFR-TKI抗性中起重要作用。此外，我们发现NSCLC中1个nAChR亚基的沉默可能会抑制尼古丁诱导的对EGFR-TKI的抗性。结论：这些结果进一步表明尼古丁在肺癌发生中的作用，并表明1 nAChR可能是EGFR-TKI治疗的生物标志物，也是吸烟相关肺癌患者的个性化靶分子。
Introduction: Nicotine, the major component among the 4000 identified chemicals in cigarette smoke, binds to nicotinic acetylcholine receptors (nAChRs) on non–small-cell lung cancer (NSCLC) cells and regulates cellular proliferation by activating mitogen-activated protein kinases [AQ: MAPK has been expanded to mitogen-activated protein kinases. Please approve.]and PI3K/Akt pathways. In patients with smoking-related lung cancer who continue smoking, the anticancer effect of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is weaker than that in nonsmokers; however, the precise reason for this difference remains unclear. We investigated the role of 1 nAChR subunit in this phenomenon. Methods: We screened for 1 nAChR mRNA in three NSCLC cell lines and analyzed the protein in resected primary NSCLC tissues. We used Western blot and RNA interference (siRNA) methodology to confirm the results. Results: We determined that 1 nAChR plays an essential role in nicotine-induced cell signaling and nicotine-induced resistance to EGFR-TKI. In addition, we showed that silencing of 1 nAChR subunit in NSCLC may suppress the nicotine-induced resistance to EGFR-TKI. Conclusions: These results further implicate nicotine in lung carcinogenesis, and suggest that 1 nAChR may be a biomarker for EGFR-TKI treatment and also a personalizing target molecule for patients with smoking-related lung cancer.