Signalling pathways involved in nicotine regulation of apoptosis human lung cancer cells
Signalling pathways involved in nicotine regulation of apoptosis human lung cancer cells
复制标题
DOI：
10.1093/carcin/19.4.551
复制
发表时间：
1998-04-01
期刊：
影响因子：
4.7
通讯作者：
Maneckjee, R
中科院分区：
文献类型：
--
作者：
Heusch, WL;Maneckjee, R
尽管尼古丁已被认为是人类肺癌发病机制中的一个潜在因素，但它在肺癌发生发展中的作用机制仍然很大程度上是未知的。本研究提供证据表明，尼古丁(A)激活肺癌细胞中的丝裂原活化蛋白(MAP)激酶信号通路，特别是细胞外信号调节激酶(ERK2)，导致这些细胞中bcl2蛋白表达增加，并抑制细胞凋亡；以及(B)阻断抗癌药物(如治疗性阿片类药物)对肺癌细胞中蛋白激酶C(PKC)和ERK2活性的抑制，从而对癌症治疗产生不利影响。尼古丁对c-jun NH2末端蛋白激酶(JNK)和p38 MAP激酶的活性似乎没有影响，这两个酶也被证明参与了细胞凋亡，而尼古丁暴露于尼古丁可导致两个已知的抑制细胞凋亡的主要信号通路(MAP激酶和PKC)的激活，尼古丁对MAP(ERK2)激酶活性的调节不依赖于PKC，这些作用发生在1MU M或更低的浓度下，通常存在于吸烟者的血液中，并可能导致细胞死亡与增殖之间的关键平衡被破坏，导致细胞失控生长。这一发现表明，在使用无烟烟草产品治疗吸烟成瘾时要谨慎，因为它们可能对早期肿瘤发展无法检测到的患者产生潜在的有害影响。
Although nicotine has been implicated as a potential factor in the pathogenesis of human lung cancer, its mechanism of action in the development of this cancer remains largely unknown. The present study provides evidence that nicotine (a) activates the mitogen-activated protein (MAP) kinase signalling pathway in lung cancer cells, specifically extracellular signal-regulated kinase (ERK2), resulting in increased expression of the bcl-2 protein and inhibition of apoptosis in these cells; and (b) blocks the inhibition of protein kinase C (PKC) and ERK2 activity in lung cancer cells by anticancer agents, such as therapeutic opioid drugs, and thus can adversely affect cancer therapy. Nicotine appears to have no effect on the activities of c-jun NH2-terminal protein kinase (JNK) and p38 MAP kinases, which have also been shown to be involved in apoptosis, While exposure to nicotine can result in the activation of the two major signalling pathways (MAP kinase and PKC) that are known to inhibit apoptosis, nicotine regulation of MAP (ERK2) kinase activity is not dependent on PKC, These effects of nicotine occur at concentrations of 1 mu M or less, that are generally found in the blood of smokers, and could lead to disruption of the critical balance between cell death and proliferation, resulting in the unregulated growth of cells. The findings suggest caution in the use of smokeless tobacco products to treat smoking addiction, as they could have a potentially deleterious effect in patients with undetectable early tumour development.