Nicotinic Receptor Ligands and Tobacco-induced Lung Cancer

烟碱受体配体与烟草诱发的肺癌

• 批准号: 8228055
• 负责人: SERGEI A GRANDO
• 金额: $ 34.08万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8228055
• 关键词: A/J Mouse; Accounting; Affinity; Apoptosis; Binding; Biological Assay; Butanones; Cancer Etiology; Case-Control Studies; Cell membrane; Cell physiology; Cell secretion; Cells; Cessation of life; Chemoprevention; Cholinergic Receptors; Chronic; Complex; Cytoplasm; Developed Countries; Development; Dose; Drug Delivery Systems; Environmental Tobacco Smoke; Epithelial Cells; Funding; Funding Applicant; Genetic; Growth; Health Hazards; Human; In Vitro; Incidence; Knowledge; Lead; Ligands; Ligation; Link; Lung; Lung Neoplasms; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Methods; Molecular; Molecular Target; N' -nitrosonornicotine; Nicotine; Nicotinic Receptors; Nitrosamines; Oncogenic; Pathway interactions; Peptides; Persons; Physiological; Play; Prevention; Process; Proteins; Regulation; Risk; Risk Factors; Role; Signal Pathway; Smoke; Smoker; Smoking; Smoking Prevention; Survival Rate; Testing; Tobacco; Tobacco-Associated Carcinogen; Tumor Promoters; Urokinase Plasminogen Activator Receptor; Work; Workplace; autocrine; cancer cell; cancer therapy; carcinogenicity; cholinergic; cigarette smoking; high risk; in vivo; lung development; malignant phenotype; men; mortality; non-smoker; novel; paracrine; prevent; public health relevance; radioligand; receptor; receptor-mediated signaling; research study; respiratory; response; smoking cessation; tumor; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Funding is requested to support our ongoing studies toward identification of molecular mechanisms mediating oncogenic effects of tobacco nitrosamines on respiratory cells and development of novel anti-cancer therapies using nicotinic acetylcholine receptor (nAChR) ligands. Preliminary studies revealed an anti-tumor potential of both canonical and non-canonical ligands of the nAChRs expressed on the cell membrane of respiratory cells. These receptors play a role in the malignant transformation of BEP2D cells caused by pharmacologic doses of the tobacco-derived carcinogenic nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The NNK-transformed and lung cancer cells are highly sensitive to apoptosis induced by the novel cholinergic peptide SLURP-1 (secreted mammalian Ly-6/urokinase plasminogen activator receptor [uPAR]-related protein). Integrating structural and functional information about SLURP-1 vs. NNK actions on respiratory cells will facilitate a better understanding of the physiologic mechanism of tumor surveillance in lungs, and may lead to the development of novel methods of prevention and treatments of tobacco-related lung cancer. We will test the following working hypotheses: 1) SLURP-1 can prevent NNK-dependent transformation of respiratory cells in vitro and in vivo; 2) cytoplasmic trapping of SLURP-1 results in altered expression of nAChRs on the plasma membrane of NNK-transformed BEP2D and lung cancer cells; 3) SLURP-1 acts as a competitive nAChR antagonist with the 17 nAChR subtype mediating most of SLURP-1 effects; and 4) SLURP-1 interferes with the receptor-mediated signaling downstream of the nAChR subtype(s) ligated by NNK in normal and malignant human respiratory cells. The Specific Aims will be to determine: 1) the role of SLURP-1 in the physiologic protection of respiratory cells from NNK carcinogenicity; 2) the molecular mechanism of increased sensitivity of malignant respiratory cells to the apoptosis induced by SLURP-1; 3) the nAChR subtype(s) mediating the pharmacologic activity of SLURP-1 and the mode of its action on the nAChRs expressed by respiratory cells; and 4) the signaling pathways downstream of the nAChRs ligated by SLURP-1 and NNK. PUBLIC HEALTH RELEVANCE: This proposal is focused on urgent problems of prevention and treatment of tobacco related lung cancer. It further develops a novel concept of receptor-mediated action of tobacco carcinogens and tumor promoters placing lung nicotinic acetylcholine receptors in the center of the pathophysiologic loop. The long-term objective is to develop pharmacologic chemoprevention of lung cancer in former smokers, and in people exposed to environmental tobacco smoke. The projected studies will ultimately establish the mechanism of anti-tumor activity of SLURP-1-an efficient, yet previously unknown, autocrine and paracrine ligand of lung nicotinic receptors capable of preventing tobacco nitrosamine-induced malignant transformation of BEP2D cells.

描述（由申请人提供）：要求资助以支持我们正在进行的研究，以鉴定识别烟草硝基胺对呼吸细胞的致癌作用以及使用烟碱乙酰胆碱受体（NACHR）的毒剂疗法的发育。初步研究表明，在呼吸细胞的细胞膜上表达的NACHR的规范和非典型配体的抗肿瘤潜力。这些受体在由烟草衍生的致癌硝基胺4-（甲基硝基氨基氨基）-1-（3-吡啶基）-1-叔丁烷（NNK）引起的BEP2D细胞的恶性转化中起作用。 NNK转化的和肺癌细胞对新型胆碱能肽SLURP-1（分泌的哺乳动物LY-6/Urokinase纤溶酶激活剂受体[UPAR]相关蛋白）诱导的细胞凋亡高度敏感。整合有关SLURP-1与NNK对呼吸细胞作用的结构和功能信息将有助于更好地理解肺中肿瘤监测的生理机理，并可能导致新的预防方法和烟草相关肺癌治疗方法的发展。我们将测试以下工作假设：1）SLURP-1可以防止NNK依赖性呼吸细胞在体外和体内的转化； 2）SLURP-1的细胞质捕获会导致NACHR在NNK转化的BEP2D和肺癌细胞的质膜上的表达改变； 3）SLURP-1充当竞争性NACHR拮抗剂，具有17个NACHR亚型介导的大部分Slurp-1效应；和4）SLURP-1干扰了NNK在正常和恶性的人呼吸细胞中结扎的NACHR亚型下游的受体介导的信号传导。具体目的是确定：1​​）SLURP-1在呼吸细胞免受NNK致癌性的生理保护中的作用； 2）恶性呼吸细胞对SLURP-1诱导的凋亡的敏感性提高的分子机制； 3）NACHR亚型介导Slurp-1的药理活性及其对呼吸细胞表达的NACHR的作用方式； 4）NACHRS下游的信号通路由Slurp-1和NNK绑扎。 公共卫生相关性：该提案的重点是预防和治疗烟草相关肺癌的紧急问题。它进一步发展了一个新的概念，即在病理生理环的中心放置肺烟碱乙酰胆碱受体的烟草致癌物和肿瘤启动子的作用。长期目标是在以前吸烟者和暴露于环境烟草烟雾的人中开发对肺癌的药理学化学预防。预计的研究最终将建立Slurp-1的抗肿瘤活性的机制，即有效但未知的肺烟碱受体的自分泌和旁分泌配体，能够防止硝基胺诱导的BEP2D细胞的恶性转化。