Role of SIRT1 in Lung Cancer Prevention by Beta-Cryptoxanthin

描述（由申请人提供）：肺癌和慢性阻塞性肺疾病（COPD）具有很强的环境风险因素（香烟烟雾暴露），COPD的存在使患肺癌的风险增加4.5倍。Sirtuin 1（SIRT 1）是一种NAD+依赖性蛋白质/组蛋白脱乙酰酶，是代谢、炎症、免疫功能、细胞凋亡和肿瘤发生的关键调节因子。据报道，SIRT 1水平在吸烟者和肺气肿/COPD患者以及暴露于烟雾的动物中降低。然而，SIRT 1在肺癌发病机制中的作用，特别是对肿瘤促进和进展的作用尚未被探索。这些信息对于SIRT 1具有促癌和抑癌双重功能的研究具有重要意义。迄今为止，还没有令人信服地证明饮食成分和药理学试剂可以预防/改变肺癌的进展。这强调了开发新的饮食预防/干预剂以对抗这种毁灭性疾病的迫切需要。从七个大型实施良好的队列中汇集的主要数据分析显示，增加饮食摄入或一种特定的叶黄素类胡萝卜素B-隐黄素（BCX）的血液水平较高，与当前吸烟者肺癌风险降低密切相关。目前尚不清楚BCX作为一种独特的生物学功能，对肺癌风险的作用涉及什么样的分子机制。我们假设SIRT 1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靶向SIRT 1信号通路作为其化学预防作用。这一假设是基于我们最近的发现，即尼古丁，烟草烟雾的主要成瘾成分，显着降低肺SIRT 1水平伴随肺气肿和增加的多样性和体积的肺肿瘤在A/J肺癌小鼠模型。重要的是，BCX治疗使尼古丁减少的肺SIRT 1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肿瘤发展。我们提出两个具体目标：1）探索SIRT 1信号通路在吸烟/尼古丁促进的肺癌发展的发病机制中的作用;和2）确定BCX调节SIRT 1信号通路作为预防肺癌发展的独特机制的能力。SIRT 1在肺部疾病中作用的研究为我们增加对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可有效靶向SIRT 1信号通路并抑制COPD和肺癌的发生，这项研究将为BCX降低肺癌风险开辟一条新的预防/干预途径。

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.