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)都是一个强烈的环境风险因素(暴露于香烟烟雾中)，COPD的存在会使患肺癌的风险增加4.5倍。Sirtuin 1(SIRT1)是一种依赖NAD+的蛋白质/组蛋白去乙酰化酶，被认为是新陈代谢、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，吸烟者、肺气肿/COPD患者以及暴露在烟雾中的动物的SIRT1水平都降低了。然而，SIRT1在肺癌发病机制中的作用，特别是在肿瘤的促进和进展中的作用还没有被探索。这些信息对于突出具有肿瘤促进和肿瘤抑制双重功能的SIRT1是非常必要的。到目前为止，还没有令人信服的饮食成分和药剂被证明可以预防/改变肺癌的进展。这强调了开发针对这种毁灭性疾病的新的饮食预防/干预剂的巨大需要。从七个实施良好的大型队列中收集的初步数据分析表明，增加饮食摄入量或提高一种特定叶黄素类胡萝卜素(Bcx)的血液水平，与当前吸烟者患肺癌的风险降低密切相关。目前尚不清楚BCX作为一种独特的生物学功能，参与抗肺癌风险的分子机制(S)是什么。我们推测SIRT1的下调是香烟烟雾/尼古丁促进肺癌发生的主要机制，而BCX则以SIRT1信号通路为化学预防作用的靶点。这一假说是基于我们最近的发现，在A/J肺癌小鼠模型中，烟草烟雾的主要成瘾成分尼古丁显著降低了伴随肺气肿的肺SIRT1水平，并增加了肺癌肿瘤的多发性和体积。重要的是，BCX治疗使尼古丁减少的肺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。我们提出了两个特定的目标：1)探讨SIRT1信号通路在吸烟/尼古丁促进的肺癌发生机制中的作用；2)确定BCX调节SIRT1信号通路的能力，作为预防肺癌发生的独特机制。对SIRT1在肺部疾病中作用的研究为我们提供了新的机会来加深我们对COPD和肺癌发病机制的了解。通过证明膳食BCX在靶向SIRT1信号通路、抑制COPD和肺癌发生方面的有效性，本研究将为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.