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。SIRT1是一种依赖NAD+的蛋白/组蛋白去乙酰化酶，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，吸烟者和肺气肿/慢性阻塞性肺病患者以及暴露于烟雾的动物的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。这一信息对于突出具有肿瘤启动子和肿瘤抑制子双重功能的SIRT1是非常需要的。到目前为止，还没有令人信服的饮食成分和药物被证明可以预防或改变肺癌的发展。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。一项来自7个大型队列的初步数据分析显示，增加饮食摄入或提高一种特定的类黄酮类胡萝卜素b-隐黄质（BCX）的血液水平与当前吸烟者肺癌风险的降低密切相关。作为一种独特的生物学功能，BCX的作用与肺癌风险相关的分子机制尚不清楚。我们假设SIRT1的下调是卷烟/尼古丁促进肺癌发病的主要机制，而BCX靶向SIRT1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，尼古丁，烟草烟雾的主要成瘾成分，在A/J肺癌小鼠模型中显著降低肺气肿伴肺SIRT1水平，增加肺肿瘤的多样性和体积。重要的是，BCX治疗将尼古丁降低的肺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肿瘤的发展。我们提出了两个具体目标：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我们进一步了解COPD和肺癌发病机制提供了新的机会。通过证明膳食BCX可有效靶向SIRT1信号通路，抑制COPD和肺癌发生，本研究将开辟BCX预防/干预降低肺癌风险的新途径。

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.