Nicotine inhibits apoptosis induced by chemotherapeutic drugs by up-regulating XIAP and survivin
Nicotine inhibits apoptosis induced by chemotherapeutic drugs by up-regulating XIAP and survivin
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DOI：
10.1073/pnas.0509313103
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发表时间：
2006-04-18
影响因子：
11.1
通讯作者：
Chellappan, S
中科院分区：
文献类型：
--
作者：
Dasgupta, P;Kinkade, R;Chellappan, S
非小细胞肺癌（NSCLC）与吸烟有很强的病因相关性。虽然尼古丁不致癌，但它可以诱导细胞增殖和血管生成，并抑制某些药物诱导的细胞凋亡。在这里，我们发现尼古丁抑制由用于治疗非小细胞肺癌的药物吉西他滨、顺铂和紫杉醇诱导的细胞凋亡。这种保护作用与尼古丁在一组人类 NSCLC 细胞系中诱导 XIAP 和生存素相关，并且 XIAP 和生存素的消耗消除了尼古丁的保护作用。尼古丁的抗凋亡作用是由二氢β-红氨酸敏感的含α3烟碱乙酰胆碱受体介导的，并且需要Akt途径。染色质免疫沉淀测定表明，尼古丁刺激导致 A549 细胞中 E2F1 募集增加，并伴随视网膜母细胞瘤肿瘤抑制蛋白 (Rb) 从生存素启动子解离。此外，E2F1水平的消除导致尼古丁对A549细胞中顺铂诱导的细胞凋亡的保护作用消失，而信号转导子和转录激活子3水平的消除则没有效果。这些研究表明，接触尼古丁可能会对化疗药物的细胞凋亡潜力产生负面影响，而生存素和 XIAP 在尼古丁的抗细胞凋亡活性中发挥着关键作用。
Non-small cell lung cancer (NSCLC) demonstrates a strong etiologic association with smoking. Although nicotine is not carcinogenic, it can induce cell proliferation and angiogenesis and suppress apoptosis induced by certain agents. Here we show that nicotine inhibits apoptosis induced by the drugs gemcitabine, cisplatin, and taxol, which are used to treat NSCLCs. This protection correlated with the induction of XIAP and survivin by nicotine in a panel of human NSCLC cell lines, and depletion of XIAP and survivin ablated the protective effects of nicotine. The antiapoptotic effects of nicotine were mediated by dihydro beta-erythroidine-sensitive alpha 3-containing nicotinic acetylcholine receptors and required the Akt pathway. Chromatin immunoprecipitation assays demonstrated that nicotine stimulation caused an increased recruitment of E2F1 and concomitant dissociation of retinoblastoma tumor suppressor protein (Rb) from survivin promoter in A549 cells. Moreover, ablation of E2F1 levels caused abrogation of the protective effects of nicotine against cisplatin-induced apoptosis in A549 cells whereas ablation of signal transducer and activator of transcription 3 levels had no effect. These studies suggest that exposure to nicotine might negatively impact the apoptotic potential of chemotherapeutic drugs and that survivin and XIAP play a key role in the antiapoptotic activity of nicotine.