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）：请求资金支持我们正在进行的研究，以鉴定介导烟草亚硝胺对呼吸细胞致癌作用的分子机制，并开发使用烟碱乙酰胆碱受体（nAChR）配体的新型抗癌疗法。初步研究揭示了呼吸细胞细胞膜上表达的 nAChR 的经典和非经典配体的抗肿瘤潜力。这些受体在药理剂量的烟草来源的致癌亚硝胺 4-(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮 (NNK) 引起的 BEP2D 细胞恶性转化中发挥作用。 NNK 转化细胞和肺癌细胞对新型胆碱能肽 SLURP-1（分泌的哺乳动物 Ly-6/尿激酶纤溶酶原激活剂受体 [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了解肺部肿瘤监测的生理机制，并可能导致开发预防和治疗与烟草相关的肺癌的新方法。我们将测试以下工作假设：1）SLURP-1可以在体外和体内阻止呼吸细胞的NNK依赖性转化； 2) SLURP-1 的细胞质捕获导致 NNK 转化的 BEP2D 和肺癌细胞质膜上 nAChR 的表达改变； 3) SLURP-1作为竞争性nAChR拮抗剂，17种nAChR亚型介导SLURP-1的大部分作用； 4) SLURP-1 干扰正常和恶性人类呼吸细胞中 NNK 连接的 nAChR 亚型下游受体介导的信号传导。具体目标是确定：1​​）SLURP-1 在生理保护呼吸细胞免受 NNK 致癌性方面的作用； 2) 恶性呼吸细胞对SLURP-1诱导的细胞凋亡敏感性增加的分子机制； 3)介导SLURP-1药理活性的nAChR亚型及其对呼吸细胞表达的nAChR的作用方式； 4) SLURP-1 和 NNK 连接的 nAChR 下游信号通路。 公共卫生相关性：该提案的重点是预防和治疗与烟草相关的肺癌的紧迫问题。它进一步发展了烟草致癌物和肿瘤促进剂受体介导作用的新概念，将肺烟碱乙酰胆碱受体置于病理生理循环的中心。长期目标是开发针对戒烟者和暴露于环境烟草烟雾的人群的肺癌的药物化学预防方法。预计的研究将最终建立 SLURP-1 的抗肿瘤活性机制，SLURP-1 是一种高效但以前未知的肺烟碱受体的自分泌和旁分泌配体，能够预防烟草亚硝胺诱导的 BEP2D 细胞恶性转化。