Role of SIRT1 in Lung Cancer Prevention by Beta-Cryptoxanthin

SIRT1 在β-隐黄质预防肺癌中的作用

• 批准号: 8636680
• 负责人: XIANG-DONG WANG
• 金额: $ 19.71万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-06 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8636680
• 关键词: A/J Mouse; Animals; Apoptosis; Biological Process; Blood; Cancer Model; Carcinogens; Carotenoids; Chemopreventive Agent; Chronic Obstructive Airway Disease; Data; Data Analyses; Development; Diet; Dietary Component; Dietary intake; Disease; Down-Regulation; Environmental Risk Factor; Epigenetic Process; Goals; Hand; Histone Deacetylase; Inflammation; Investigation; Knowledge; Lung; Lung Neoplasms; Lung diseases; Malignant neoplasm of lung; Mediating; Metabolism; Molecular; Molecular Target; Mouse Strains; Mus; Nicotine; Pathogenesis; Patients; Play; Point Mutation; Population; Preventive; Preventive Intervention; Proteins; Pulmonary Emphysema; Recruitment Activity; Reporting; Research; Research Personnel; Risk; Role; Signal Pathway; Smoke; Smokeless Tobacco; Smoker; Time; Tobacco smoke; Tobacco smoking; Tumor Promoters; Tumor Promotion; Tumor Suppressor Proteins; Up-Regulation; Work; Xanthophylls; base; beta-cryptoxanthin; cancer risk; cigarette smoking; cohort; cryptoxanthin; evidence base; experience; fruits and vegetables; immune function; lung cancer prevention; lung carcinogenesis; lung tumorigenesis; mouse model; novel; prevent; protective effect; public health relevance; tumor; tumor progression

DESCRIPTION (provided by applicant): Lung cancer and chronic obstructive pulmonary disease (COPD) share a strong environmental risk factor (cigarette smoke exposure) and the presence of COPD increases the risk of developing lung cancer up to 4.5 times. Sirtuin 1 (SIRT1), a NAD+-dependent protein/histone deacetylase, has been implicated as a key regulator of metabolism, inflammation, immune function, apoptosis, and tumor development. It has been reported that SIRT1 levels were reduced in smokers and emphysema/COPD patients as well as in animals exposed to smoke. However, the role of SIRT1 in the pathogenesis of lung cancer, specifically, on tumor promotion and progression has not been explored. This information is greatly needed in the highlighting of SIRT1 with dual functions in tumor promoter and tumor suppressor. There are no dietary components and pharmacological agents so far that have convincingly been shown to prevent/alter the progress of lung cancer. This emphasizes the great need for the development of new dietary prevention/intervention agents against this devastating disease. A primary data analysis pooled from seven large well-implemented cohorts showed that increased dietary intake or higher blood levels of one specific xanthophylls carotenoid, b- cryptoxanthin (BCX), is strongly associated with a reduced risk of lung cancer in current smokers. It is not clear what molecular mechanism(s) is involved in BCX action, as a unique biological function, against lung cancer risk. We hypothesize that the down-regulation of SIRT1 is a major mechanism involved in the pathogenesis of the lung cancer promotion by cigarette smoke/nicotine, whereas BCX targets SIRT1 signaling pathway as its chemopreventive action. This hypothesis has been based on our recent findings that nicotine, the main addictive component of tobacco smoke, markedly reduced lung SIRT1 levels accompanying with emphysema and increased both multiplicity and volume of lung tumors in the A/J lung cancer mouse model. Importantly, BCX treatment restored nicotine-reduced lung SIRT1 protein to normal levels and inhibited both nicotine-induced emphysema and nicotine-promoted lung tumor development. We propose two specific aims: 1) Explore the role of SIRT1 signaling pathway in pathogenesis of smoke/nicotine- promoted lung cancer development; and 2) Determine the ability of BCX to modulate SIRT1 signaling pathway as a unique mechanism for prevention of lung cancer development. The investigation of the role of SIRT1 in lung diseases offers novel opportunities to increase our understanding of mechanisms involved in the pathogenesis of COPD and lung cancer. By demonstrating that dietary BCX is effective in targeting the SIRT1 signaling pathway and inhibiting COPD and lung carcinogenesis, this research will open a new prevention/intervention avenue of BCX to reduce lung cancer risk.

描述（由申请人提供）：肺癌和慢性阻塞性肺病（COPD）有一个很强的环境风险因素（香烟烟雾暴露），并且慢性阻塞性肺病的存在会使患肺癌的风险增加高达 4.5 倍。 Sirtuin 1 (SIRT1) 是一种 NAD+ 依赖性蛋白/组蛋白脱乙酰酶，被认为是代谢、炎症、免疫功能、细胞凋亡和肿瘤发展的关键调节因子。据报道，吸烟者、肺气肿/慢性阻塞性肺病患者以及接触烟雾的动物中 SIRT1 水平降低。然而，SIRT1在肺癌发病机制中的作用，特别是在肿瘤促进和进展中的作用尚未被探索。这些信息对于强调 SIRT1 具有肿瘤启动子和肿瘤抑制子的双重功能非常需要。迄今为止，尚无任何饮食成分和药物已被令人信服地证明可以预防/改变肺癌的进展。这强调了开发新的饮食预防/干预剂来对抗这种毁灭性疾病的巨大需求。对七个实施良好的大型队列进行的主要数据分析表明，增加膳食摄入量或提高一种特定叶黄素类胡萝卜素、β-隐黄质 (BCX) 的血液水平与当前吸烟者患肺癌风险的降低密切相关。目前尚不清楚 BCX 作为一种独特的生物学功能，对抗肺癌风险涉及哪些分子机制。我们假设 SIRT1 的下调是香烟烟雾/尼古丁促进肺癌发病机制的主要机制，而 BCX 则以 SIRT1 信号通路作为其化学预防作用。这一假设基于我们最近的发现，即烟草烟雾中的主要成瘾成分尼古丁显着降低了 A/J 肺癌小鼠模型中伴随肺气肿的肺部 SIRT1 水平，并增加了肺部肿瘤的多样性和体积。重要的是，BCX 治疗将尼古丁减少的肺部 SIRT1 蛋白恢复到正常水平，并抑制尼古丁诱导的肺气肿和尼古丁促进的肺部肿瘤的发展。我们提出两个具体目标：1）探索SIRT1信号通路在烟雾/尼古丁促进肺癌发生的发病机制中的作用； 2) 确定 BCX 调节 SIRT1 信号通路的能力作为预防肺癌发展的独特机制。 SIRT1 在肺部疾病中的作用的研究为加深我们对 COPD 和肺癌发病机制的理解提供了新的机会。通过证明膳食BCX可以有效靶向SIRT1信号通路并抑制COPD和肺癌发生，这项研究将为BCX开辟一条新的预防/干预途径，以降低肺癌风险。