Increased inducible nitric oxide synthase in lung carcinoma of smokers
Increased inducible nitric oxide synthase in lung carcinoma of smokers
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DOI：
10.1002/cncr.23166
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发表时间：
2008-01-15
期刊：
影响因子：
6.2
通讯作者：
Yim, Anthony R. C.
中科院分区：
文献类型：
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作者：
Chen, George G.;Lee, Tak Wai;Yim, Anthony R. C.
背景众所周知，吸烟在肺癌的发展中起着重要作用。诱导型一氧化氮合酶（Inducible nitric oxide synthase，iNOS）可促进或抑制细胞增殖和生长，其在恶性肿瘤发生发展中的作用存在争议。吸烟与人肺癌中iNOS的关系尚不清楚。方法.该研究检测了吸烟者和非吸烟者的非小细胞肺癌（NSCLC）组织中的iNOS/NO水平，以及用4-（N-甲基-N-亚硝胺）-1-（3-吡啶基）-1-丁酮（NNK）（一种强效烟草特异性致癌物）处理的NSCLC细胞（NCI-H23）中的iNOS/NO水平。结果吸烟者肺癌组织中iNOS/NO水平显著高于非吸烟者。与iNOS/NO不同，前者的caspase-3活性较后者降低。在用NO供体S-亚硝基-N-乙酰青霉胺（SNAP）处理的NCI-H23细胞中，裂解的caspase-3的表达下降，而用NO抑制剂NG-甲基-L-精氨酸（NMA）处理引起裂解的caspase-3的增加。与caspase-3的变化一致，SNAP处理抑制了Uhoc 1诱导的细胞死亡，Uhoc 1是一种有效的细胞死亡诱导剂。NMA处理大大增强了细胞对Uhoc 1的敏感性。此外，经NNK处理的细胞显示iNOS蛋白增加，伴随着细胞增殖的升高。结论.研究表明，吸烟可促进iNOS/NO水平的升高，但抑制caspase-3的活性，这可能导致肺癌细胞的增殖和生长。
BACKGROUND. Cigarette smoking is well known to play an important role in the development of lung cancer. Inducible nitric oxide synthase (iNOS) can either promote or inhibit cell proliferation and growth, which makes its role in the development of malignant tumors controversial. The relation between cigarette smoking and iNOS in human lung cancer is unknown. METHODS. The study examined the levels of iNOS/NO in nonsmall-cell lung cancer (NSCLC) tissues of smokers and nonsmokers and in NSCLC cells (NCI-H23) treated by 4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a potent tobacco-specific carcinogen. RESULTS. The level of iNOS/NO was significantly higher in lung cancer tissues of smokers than that of nonsmokers. Unlike iNOS/NO, the activity of caspase-3 was reduced in the former compared with the latter. The expression of the cleaved caspase-3 was deceased in NCI-H23 cells treated with S-Nitroso-N-acetylpenicillamine (SNAP), an NO donor, whereas treatment with NG-methyl-L-arginine (NMA), an NO inhibitor, caused an increase in cleaved caspase-3. Consistent with the change in caspase-3, SNAP treatment inhibited cell death induced by UCNO1, a potent cell death-inducer. NMA treatment greatly enhanced the sensitivity of the cells to UCNO1. Further, the cells treated by NNK showed an increase in iNOS protein, accompanied by an elevation of cell proliferation. CONCLUSIONS. The study demonstrates that cigarette smoking promotes the level of iNOS/NO but suppresses the activity of caspase-3, which may lead to the proliferation and growth of lung cancer cells.