Role of SIRT1 in Lung Cancer Prevention by Beta-Cryptoxanthin

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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.