Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells
Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells
复制标题
DOI：
10.1172/jci200316147
复制
发表时间：
2003-01-01
影响因子：
15.9
通讯作者：
Dennis, PA
中科院分区：
文献类型：
--
作者：
West, KA;Brognard, J;Dennis, PA
与烟草有关的疾病，如肺癌，每年导致超过420万人死亡，其中美国每年约有40万人死亡。烟草成分的遗传毒性作用已被描述，但对正常细胞信号通路的影响尚未描述。本研究显示，香烟烟雾、尼古丁和烟草特异性致癌物4-（甲基亚硝胺）-1-（3-吡啶基）-1-丁酮（NNK）两种成分激活了体外非永生化人气道上皮细胞中的丝氨酸/苏氨酸激酶Akt。在吸烟者可达到的浓度下，尼古丁或NNK在几分钟内激活Akt，分别依赖于含有α (3)-/ α(4)-或含有α(7)-的尼古丁乙酰胆碱受体。活化的Akt增加了下游底物GSK-3、p70（S6K）、4EBP-1和FKHR的磷酸化。用尼古丁或NNK治疗可减轻依托泊苷、紫外线照射或过氧化氢引起的细胞凋亡，并部分诱导转化表型，表现为接触抑制的丧失、对外源生长因子的依赖或对ECM的依从性的丧失。体内，在nnk处理的A/J小鼠的气道上皮细胞和肺肿瘤以及吸烟者衍生的人肺癌中检测到活性Akt。尼古丁和NNK对Akt的冗余激活可能通过调节肿瘤发生、细胞生长和凋亡的两个关键过程来促进烟草相关癌变。
Tobacco-related diseases such as lung cancer cause over 4.2 million deaths annually, with approximately 400,000 deaths per year occurring in the US. Genotoxic effects of tobacco components have been described, but effects on signaling pathways in normal cells have not been described. Here, we show activation of the serine/threonine kinase Akt in nonimmortalized human airway epithelial cells in vitro by two components of cigarette smoke, nicotine and the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Activation of Akt by nicotine or NNK occurred within minutes at concentrations achievable by smokers and depended upon alpha(3)-/alpha(4)-containing or alpha(7)-containing nicotinic acetylcholine receptors, respectively. Activated Akt increased phosphorylation of downstream substrates such as GSK-3, p70(S6K), 4EBP-1, and FKHR. Treatment with nicotine or NNK attenuated apoptosis caused by etoposide, ultraviolet irradiation, or hydrogen peroxide and partially induced a transformed phenotype manifest as loss of contact inhibition and loss of dependence on exogenous growth factors or adherence to ECM. In vivo, active Akt was detected in airway epithelial cells and lung tumors from NNK-treated A/J mice, and in human lung cancers derived from smokers. Redundant Akt activation by nicotine and NNK could contribute to tobacco-related carcinogenesis by regulating two processes critical for tumorigenesis, cell growth and apoptosis.