Role of Beta-arrestin-1 and Src in nAChR Signaling and Lung Caancer

Beta-arrestin-1 和 Src 在 nAChR 信号传导和肺癌中的作用

基本信息

批准号：
8016094
负责人：
SRIKUMAR P. CHELLAPPAN
金额：
$ 33.61万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-17 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8016094
关键词：
A549 Accounting Adhesions Affect Apoptosis Apoptotic Arrestin Beta 1 Biochemical Biological Assay Blood Vessels Butanones Carcinogens Cardiovascular Diseases Cell Culture System Cell Line Cell Nucleus Cell Proliferation Cells Colorectal Cancer Development Disease Epithelial Event Exposure to Functional disorder G Protein-Coupled Receptor Signaling Gene Expression Gene Expression Regulation Growth Health Immigration In Vitro Lead Light Lung Lung Neoplasms Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of lung Mediating Mesenchymal Molecular Molecular Target Mus N&apos -nitrosonornicotine Neoplasm Metastasis Neuroglia Nicotine Nicotinic Receptors Non-Small-Cell Lung Carcinoma Nuclear Translocation Oncogenic Patients Play Process Property Proteins Relative (related person)Reporting Resistance Role Scaffolding Protein Signal Transduction Smoker Smoking System Tobacco Tobacco smoke Tobacco use Tobacco-Associated Carcinogen Transcriptional Activation Tumor Angiogenesis Tumor Cell Invasion Tyrosine Phosphorylation angiogenesis arrestin 1 base cancer cell chemotherapeutic agent cigarette smoking combat computerized data processing in vivo insight mouse model novel promoter receptor research study response smoking cessation src-Family Kinases tissue/cell culture tumor tumor growth tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Cigarette smoking is strongly correlated with onset of lung cancer and cardiovascular diseases. About 60% of non-small cell lung carcinomas (NSCLCs) arise as a result of smoking. Nicotine and structurally related tobacco carcinogens like 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) have been found to induce the proliferation of cell lines derived from lung cancers. In addition, these agents could induce angiogenesis in vitro and in vivo and confer resistance to apoptosis. These events are mediated through the activation of the nicotinic acetylcholine receptors (nAChRs), and nAChRs have been detected in a variety of non-neuronal cells. Nicotine by itself is not known to induce oncogenesis; but based on its ability to induce tumor growth and angiogenesis, we propose to study how nicotine affects the growth, progression and metastasis of non-small cell lung carcinomas. Our recent results show that the scaffolding protein ¿-arrestin-1 plays a major role in mediating the proliferative signals of nAChRs and was necessary for activation of Src in response to nAChR stimulation. Further, nicotine stimulation of A549 cells led to changes in the expression of genes involved in epithelial-mesenchymal transition (EMT). Recent studies have shown that ¿-arrestin-1 plays a significant role in the metastasis of colorectal cancers. Given this background, we will assess the role of ¿-arrestin-1 and Src in nicotine-induced cell proliferation, tumor cell invasion, metastasis and angiogenesis. It has been reported that ¿-arrestin-1 translocates to the nucleus in response to G-protein coupled receptor signaling and activates multiple promoters; we find a similar nuclear translocation upon nicotine stimulation. Our preliminary results show that nAChR stimulation of non-small cell lung carcinoma cells leads to transcriptional activation of promoters involved in proliferation and EMT; we will assess the contribution of ¿-arrestin-1 to this process. Based on our finding that nicotine can promote the growth of non-small cell lung tumors in mice, we will examine whether nicotine promotes tumor progression and metastasis in three different mouse models. Underlying mechanisms facilitating these processes will be elucidated, including the contribution of ¿-arrestin-1 and Src in nicotine-induced tumor metastasis. Since a majority of non-small cell lung carcinomas correlate with exposure to tobacco smoke, these studies will throw light on the molecular mechanisms by which nicotine affects the growth and progression of lung cancers. PUBLIC HEALTH RELEVANCE: Exposure to tobacco smoke is highly correlated with onset of lung cancer. Though it is the direct effect of tobacco carcinogens that initiate tumor formation, exposure to nicotine might facilitate the growth and progression of tumors already formed. This is especially relevant since many smokers use nicotine supplements to quit smoking. The studies proposed in this application will elucidate the mechanisms by which nicotine induces cell proliferation, tumor growth and spread, as well as formation of new blood vessels. These studies can be expected to lead to the development of novel agents to combat cancer.

描述（由申请人提供）：吸烟与肺癌和心血管疾病的发病密切相关，大约 60% 的非小细胞肺癌 (NSCLC) 是由吸烟和结构相关的烟草致癌物（如 4-）引起的。 (甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮 (NNK) 和 N'-亚硝基降烟碱 (NNN) 已被发现可诱导增殖此外，这些药物可以在体外和体内诱导血管生成，并通过激活烟碱乙酰胆碱受体 (nAChR) 介导，并且已在多种细胞中检测到 nAChR。目前尚不清楚尼古丁本身会诱导肿瘤发生；但基于其诱导肿瘤生长和血管生成的能力，我们建议研究尼古丁如何影响生长，我们最近的研究结果表明支架蛋白 ¿ -arrestin-1 在介导 nAChR 的增殖信号中发挥着重要作用，并且是响应 nAChR 刺激而激活 Src 所必需的。此外，A549 细胞的尼古丁刺激导致参与上皮间质转化的基因表达发生变化。最近的研究表明 ¿ -arrestin-1 在结直肠癌的转移中发挥重要作用鉴于此背景，我们将评估 ¿据报道，arrestin-1和Src在尼古丁诱导的细胞增殖、肿瘤细胞侵袭、转移和血管生成中的作用。 -arrestin-1 响应 G 蛋白偶联受体信号转位至细胞核并激活多个启动子；我们的初步结果表明，nAChR 刺激非小细胞肺癌细胞会导致转录。参与增殖和 EMT 的启动子的激活；我们将评估 ¿基于我们发现尼古丁可以促进小鼠非小细胞肺癌的生长，我们将研究尼古丁是否会在三种不同的小鼠模型中促进肿瘤进展和转移。予以阐明，包括 ¿ 的贡献-arrestin-1 和 Src 在尼古丁诱导的肿瘤转移中的作用由于大多数非小细胞肺癌与接触烟草烟雾有关，这些研究将揭示尼古丁影响肺癌生长和进展的分子机制。公共卫生相关性：接触烟草烟雾与肺癌的发病高度相关，尽管烟草致癌物质的直接作用会引发肿瘤形成，但接触尼古丁可能会促进肺癌的生长和进展。这尤其重要，因为许多吸烟者使用尼古丁补充剂来戒烟，该申请中提出的研究将阐明尼古丁诱导细胞增殖、肿瘤生长和扩散以及新血管形成的机制。预计研究将导致抗癌新药的开发。