Lung cancer is a heavy health burden due to its high incidence and poor prognosis. Development of effective preventive approaches is an urgent need. Most lung cancers are associated with cigarette smoking, which creates chronic pulmonary inflammation, a critical event in lung carcinogenesis where cytokines play a pivotal role. Therefore, blocking cigarette smoke-induced pro-tumorigenic cytokine production could be an important approach in cancer prevention. Recent studies highlight Interleukin 6 (IL-6) as playing a central role in the development of lung cancer. IL-6 can be secreted by several cell types including fibroblasts, a key component in the inflammatory microenvironment. Our preliminary study shows that cigarette smoke carcinogen bezo[a]pyrene diol epoxide (BPDE) robustly stimulates IL-6 secretion from normal human lung fibroblasts. Importantly, we found that this effect of BPDE can be potently inhibited by quercetin, a flavonoid found in vegetables and fruits. Quercetin also suppresses IL-6-induced Stat3 activation in human bronchial epithelial cells (HBECs). Although quercetin has been suggested to possess lung cancer prevention properties in population and animal studies, the underlying mechanism is not well elucidated. We hypothesize that quercetin prevents lung cancer through inhibiting carcinogen-induced IL-6 secretion from lung fibroblasts and inhibiting the IL-6/Stat3 signaling pathway in HBECs. We will test this hypothesis in three Specific Aims: 1) To determine if quercetin suppresses transformation of HBECs through inhibiting BPDE-induced IL-6 secretion from lung fibroblasts and IL-6 signaling in HBECs;2) To determine if quercetin blocks BPDE-induced IL-6 secretion from lung fibroblasts through inhibition of the NF-?B and ERK signal pathways;3) To determine if quercetin inhibits lung cancer formation and suppresses IL-6 secretion and signaling in vivo. This study will reveal the novel function of quercetin in modulating carcinogen-induced cytokine production in a tumor microenvironment, and help to develop new strategies for lung cancer chemoprevention.
This application will investigate if quercetin, a dietary compound, prevents lung carcinogenesis through inhibiting tobacco carcinogen-induced Interleukin-6 secretion in human lung fibroblasts, and through suppressing Interleukin-6 signaling pathway in bronchial epithelial cells. This project will help to develop quercetin as a potential chemopreventive agent for lung cancer.
|Chen, Wenshu; Padilla, Mabel T; Xu, Xiuling et al. (2016) Quercetin inhibits multiple pathways involved in interleukin 6 secretion from human lung fibroblasts and activity in bronchial epithelial cell transformation induced by benzo[a]pyrene diol epoxide. Mol Carcinog 55:1858-1866|
|Leng, Shuguang; Thomas, Cynthia L; Snider, Amanda M et al. (2016) Radon Exposure, IL-6 Promoter Variants, and Lung Squamous Cell Carcinoma in Former Uranium Miners. Environ Health Perspect 124:445-51|
|Chen, W; Wang, Q; Bai, L et al. (2014) RIP1 maintains DNA integrity and cell proliferation by regulating PGC-1?-mediated mitochondrial oxidative phosphorylation and glycolysis. Cell Death Differ 21:1061-70|