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：
8208242
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 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8208242
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 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

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. Expsoure 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 faciliate 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.

吸烟与肺癌和心血管疾病的发病密切相关。约60% 非小细胞肺癌 (NSCLC) 是由吸烟引起的。尼古丁及其结构相关烟草致癌物质，如 (4-(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) 已被发现可诱导肺癌细胞系的增殖。此外，这些药物可以在体外和体内诱导血管生成并赋予细胞凋亡抵抗力。这些事件是通过烟碱乙酰胆碱受体 (nAChR) 的激活介导，nAChR 已被在多种非神经元细胞中检测到。目前尚不清楚尼古丁本身会诱发肿瘤发生。但基于由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，非小细胞肺癌的进展和转移。我们最近的研究结果表明，脚手架蛋白 β-arrestin-1 在介导 nAChR 的增殖信号中起主要作用，并且对于响应 nAChR 刺激而激活 Src。此外，尼古丁刺激 A549 细胞导致参与上皮间质转化（EMT）的基因的表达。最近的研究表明 β-arrestin-1在结直肠癌的转移中发挥重要作用。在此背景下，我们将评估 β-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。据报道，β-arrestin-1 响应 G 蛋白而易位至细胞核耦合受体信号传导并激活多个启动子；我们发现类似的核易位尼古丁刺激。我们的初步结果表明 nAChR 刺激非小细胞肺癌细胞导致参与增殖和 EMT 的启动子转录激活；我们将评估 β-arrestin-1 对此过程的贡献。根据我们的发现，尼古丁可以促进非在小鼠小细胞肺癌中，我们将研究尼古丁是否促进肿瘤进展和转移三种不同的鼠标型号。将阐明促进这些过程的基本机制，包括 β-arrestin-1 和 Src 在尼古丁诱导的肿瘤转移中的作用。由于大多数非小蜂窝肺癌与接触烟草烟雾有关，这些研究将揭示分子机制尼古丁影响肺癌生长和进展的机制。接触烟草烟雾与肺癌的发病高度相关。虽然它是烟草致癌物质引发肿瘤形成的直接影响，接触尼古丁可能会促进已经形成的肿瘤的生长和进展。这是特别重要的是，因为许多吸烟者使用尼古丁补充剂来戒烟。这本申请中提出的研究将阐明尼古丁的作用机制诱导细胞增殖、肿瘤生长和扩散以及新血液的形成船只。这些研究预计将导致新型药物的开发对抗癌症。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Nicotine-Mediated Regulation of Nicotinic Acetylcholine Receptors in Non-Small Cell Lung Adenocarcinoma by E2F1 and STAT1 Transcription Factors.

E2F1 和 STAT1 转录因子对非小细胞肺腺癌中烟碱乙酰胆碱受体的尼古丁介导调节。

DOI：
发表时间：
2016
期刊：
影响因子：
3.7
作者：
Schaal, Courtney;Chellappan, Srikumar
通讯作者：
Chellappan, Srikumar

Genetic and biochemical alterations in non-small cell lung cancer.

非小细胞肺癌的遗传和生化改变。

DOI：
发表时间：
2012
期刊：
影响因子：
3
作者：
Johnson, Jackie L;Pillai, Smitha;Chellappan, Srikumar P
通讯作者：
Chellappan, Srikumar P

YAP1 Regulates OCT4 Activity and SOX2 Expression to Facilitate Self-Renewal and Vascular Mimicry of Stem-Like Cells.

YAP1 调节 OCT4 活性和 SOX2 表达，促进干细胞样细胞的自我更新和血管模仿。

DOI：
发表时间：
2015-06
期刊：
影响因子：
0
作者：
Bora;Nguyen, Jonathan;Schaal, Courtney;Perumal, Deepak;Singh, Sandeep;Coppola, Domenico;Chellappan, Srikumar
通讯作者：
Chellappan, Srikumar

ChIP on chip and ChIP-Seq assays: genome-wide analysis of transcription factor binding and histone modifications.

芯片上 ChIP 和 ChIP-Seq 检测：转录因子结合和组蛋白修饰的全基因组分析。