Schuller H M, Tithof P K, Williams M, Plummer H
Experimental Oncology Laboratory, College of Veterinary Medicine, University of Tennessee, Knoxville 37996, USA.
Cancer Res. 1999 Sep 15;59(18):4510-5.
Lung cancer is the leading cause of death in the United States, and it demonstrates a strong etiological association with smoking. The nicotine-derived nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) reproducibly induces pulmonary adenocarcinomas (ACs) in laboratory rodents and is considered an important contributing factor to the high lung cancer burden observed in smokers. It has been shown that the development of NNK-induced ACs in mice is reduced by inhibitors of cyclooxygenase and lipoxygenase and that the growth of human AC cell lines is regulated by beta-adrenergic receptors. On the basis of structural similarities of NNK with classic beta-adrenergic agonists, we tested the hypothesis that NNK stimulates the growth of human AC cells via agonist-binding to beta-adrenergic receptors, resulting in the release of arachidonic acid (AA). In support of this hypothesis, radioreceptor assays with transfected CHO cell lines stably expressing the human beta1- or beta2-adrenergic receptor demonstrated high affinity binding of NNK to each of these receptors. Two human AC cell lines expressed beta1- and beta2-adrenergic receptors by reverse transcription-PCR and responded to NNK with the release of AA and an increase in DNA synthesis. Beta-adrenergic antagonists completely blocked the release of AA and increase in DNA synthesis. The cyclooxygenase inhibitor aspirin and the 5-lipoxygenase inhibitor MK-886 both partially inhibited DNA synthesis in response to NNK. Our findings identify the direct interaction of NNK with beta-adrenergic, AA-dependent pathways as a novel mechanism of action which may significantly contribute to the high cancer-causing potential of this nitrosamine. Moreover, NNK may also contribute to the development of smoking-related nonneoplastic disease via this mechanism.
肺癌是美国主要的死因，并且它与吸烟有着很强的病因学关联。尼古丁衍生的亚硝胺4-(甲基亚硝氨基)-1-(3-吡啶基)-1-丁酮（NNK）可在实验啮齿动物中反复诱发肺腺癌（AC），并被认为是吸烟者中观察到的高肺癌负担的一个重要促成因素。研究表明，环氧化酶和脂氧合酶抑制剂可减少小鼠中NNK诱发的AC的发生，并且人AC细胞系的生长受β-肾上腺素能受体调节。基于NNK与经典β-肾上腺素能激动剂的结构相似性，我们检验了以下假设：NNK通过与β-肾上腺素能受体激动剂结合刺激人AC细胞的生长，从而导致花生四烯酸（AA）的释放。为支持这一假设，对稳定表达人β1或β2肾上腺素能受体的转染CHO细胞系进行的放射受体分析表明，NNK与这些受体中的每一个都有高亲和力结合。两种人AC细胞系通过逆转录聚合酶链反应表达β1和β2肾上腺素能受体，并对NNK作出反应，释放AA并增加DNA合成。β-肾上腺素能拮抗剂完全阻断了AA的释放和DNA合成的增加。环氧化酶抑制剂阿司匹林和5-脂氧合酶抑制剂MK-886均部分抑制了对NNK的DNA合成反应。我们的研究结果确定了NNK与β-肾上腺素能、AA依赖性途径的直接相互作用是一种新的作用机制，这可能对这种亚硝胺的高致癌潜力有显著贡献。此外，NNK也可能通过这种机制导致吸烟相关的非肿瘤性疾病的发生。
