Nicotine, nicotinic receptors and lung cancer

尼古丁、烟碱受体与肺癌

• 批准号: 8444358
• 负责人: ELIOT R SPINDEL
• 金额: $ 42.01万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-04 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444358
• 关键词: A/J Mouse; Acetylcholine; Adenocarcinoma; Adenocarcinoma Cell; Affect; Alleles; Amino Acids; Attention; Binding; Calcium; Cancer Cell Growth; Cancer Etiology; Cancer cell line; Cell Line; Cell Proliferation; Cell physiology; Cells; Cellular biology; Cessation of life; Cigarette; Code; Data; Development; Electrophysiology (science); Event; Gated Ion Channel; Gene Cluster; Genetic Polymorphism; Genotype; Growth; Growth and Development function; In Vitro; Ion Channel; Knock-in Mouse; Laboratories; Lentivirus Vector; Ligands; Link; Lung Adenocarcinoma; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mutate; Mutation; Neuroglia; Neurotransmitter Receptor; Nicotine; Nicotinic Agonists; Nicotinic Receptors; Non-Small-Cell Lung Carcinoma; Nude Mice; Oregon; Pathway interactions; Pattern; Phenotype; Phosphotransferases; Primates; Receptor Gene; Receptor Signaling; Research; Risk; Role; Seminal; Smoke; Smoker; Smoking; Squamous Cell Lung Carcinoma; Stimulus; Testing; Tobacco smoke; Transgenic Mice; United States; cancer cell; cancer risk; cell type; cigarette smoking; genome wide association study; in vivo; interest; knock-down; lung small cell carcinoma; mutant; novel therapeutic intervention; public health relevance; receptor; receptor binding; receptor expression; response; tumor; tumor growth

DESCRIPTION (provided by applicant): The overwhelming majority of lung cancers are associated with smoking and most lung cancers express nicotinic acetylcholine receptors (nAChR) that are activated by the nicotine in cigarette smoke. The objective of this application is to characterize how the interaction of nicotine with nicotinic acetylcholine receptors (nAChR) expressed by lung cancers stimulates tumor growth with the ultimate objective of developing new therapeutic approaches to lung cancer by blocking this proliferative pathway. The nicotinic receptors are ligand-gated ion channels composed of 5 subunits, either a mixture of a and ¿ subunits or 5 of the same a subunit. Binding of a nicotinic agonist such as acetylcholine or nicotine opens the ion channel allowing entry of Na+ or Ca++ into the cell. While the nAChR are best known for their role as neurotransmitter receptors in the CNS, they are also widely expressed in non-neuronal cells. Our laboratory has been a leader in showing that essentially all lung cancers express nAChR and binding of nicotine to the nAChR stimulates lung cancer growth. The real world importance of nicotine as a stimulus for lung cancer growth has recently been confirmed by multiple genome-wide association studies linking polymorphisms in nicotinic receptors to increased risk of lung cancer even when corrected for numbers of cigarettes smoked. Strongest linkage by far has been with polymorphisms in the 15q25.1 nicotinic receptor gene cluster that encodes thea3, a5 and ¿4 nAChR subunits. Critically, the exact role of these nAChR subunits in mediating the ability of nicotine to stimulate cancer growth is unknown. In addition, how the polymorphism of greatest interest, rs16969968 which changes the Asp at residue 398 (a5D398) of the 15 nAChR subunit to Asn (a5N398) affects lung cancer growth is totally unknown. It is also likely that besides the a5D398 to a5N398 mutation, other mutations occur in the 15q25.1 nAChR gene locus that affects lung cancer growth. Therefore, we propose the following 3 specific aims: 1, To determine which nicotinic receptor subtypes in the a3, a5 and ¿4 nAChR gene locus are required for nicotine to stimulate lung cancer growth; 2, To determine the role of the a5D398 to a5N398 mutation (rs16969968) in mediating increased growth and development of lung cancer; and 3, To determine if there are additional common polymorphisms in the a3, a5 and ¿4 nAChR subunits that may increase lung cancer responses to nicotine. Because non-small cell lung cancer (NSCLC) is much more frequent than small cell lung carcinoma (SCLC) we will focus on NSCLC and specifically on squamous cell lung carcinoma (SCC) and lung adenocarcinoma (AC) which are the most frequent forms of NSCLC. These aims will be accomplished using a mix of cell biology, electrophysiology and in vivo studies in nude and transgenic mice to characterize actions of the nAChR receptors in lung cancer. From these studies will come understanding of which nAChR receptors mediate the effects of nicotine on lung cancer growth and thus identify which nAChR and proliferative pathways can be effectively targeted to develop new therapeutic approaches for lung cancer.

描述（通过应用提供）：绝大多数肺癌与吸烟有关，大多数肺癌表达烟碱乙酰胆碱受体（NACHR），这些乙酰胆碱受体（NACHR）在香烟烟雾中被尼古丁激活。该应用的目的是表征尼古丁与肺癌表达的尼古丁乙酰胆碱受体（NACHR）的相互作用如何通过阻止这种增殖途径来开发新的肺癌治疗方法来刺激肿瘤的生长。烟碱受体是由5个亚基组成的配体门控离子通道，即A和€亚基的混合物或5个亚基。烟碱激动剂（例如乙酰胆碱或尼古丁）的结合打开离子通道，允许将Na+或Ca ++进入细胞。虽然NACHR以其CNS中神经递质接收器的作用而闻名，但它们在非神经元细胞中也广泛表达。我们的实验室一直是一个领导者，表明所有肺癌基本上表达NACHR和尼古丁对NACHR的结合刺激肺癌，尼古丁作为肺癌生长的刺激性的现实世界的重要性已通过多种基因组的关联研究来证实，即使在尼古丁受体中增加了肺癌的风险，即使在烟雾中增加了烟雾的风险，即到目前为止，最强的联系是在编码TheA3，A5和4 NACHR亚基的15q25.1烟碱受体基因簇中的多态性。至关重要的是，这些NACHR亚基在介导尼古丁刺激癌症生长的能力中的确切作用尚不清楚。此外，最大兴趣的多态性是如何改变15个NACHR亚基的住所398（A5D398）的ASN（A5N398）的ASP的RS16969968（A5N398）影响肺癌的生长，这是完全未知的。除了A5D398至A5N398突变外，其他突变还可能发生在影响肺癌生长的15q25.1 NACHR基因基因座。因此，我们提出以下3个特定目的：1，以确定A3，A5和4 NACHR基因基因座中的哪些烟碱受体亚型才能刺激肺癌的生长。 2，确定A5D398至A5N398突变（RS16969968）在介导肺癌的生长和发展中的作用； 3，确定在A3，A5和4 NACHR亚基中是否还有其他常见的多态性，可能会增加肺癌对尼古丁的反应。由于非小细胞肺癌（NSCLC）比小细胞肺癌（SCLC）要高得多，因此我们将重点放在NSCLC上，特别是鳞状细胞肺癌（SCC）和肺腺癌（AC），这是NSCLC最常见的形式。这些目标将使用细胞生物学，电生理学和体内研究的混合物来实现，以表征NACHR受体在肺癌中的作用。从这些研究中将了解哪种NACHR受体介导尼古丁对肺癌生长的影响，从而确定可以有效地针对哪种NACHR和增殖的途径来开发新的肺癌治疗方法。