title: Lasting glycolytic stress governs susceptibility to urethane-induced lung carcinogenesis in vivo and in vitro.
abstract: Urethane is a recognized genotoxic carcinogen in fermented foods and beverages. This study is to compare susceptibility of ICR mice, BALB/c mice and C57BL/6 mice to urethane-induced lung carcinogenesis. The mice were injected intraperitoneally with 600 mg/kg of urethane for three times or ten times at 7-day intervals. At week 26, lung carcinogenic incidence was found in 40% ICR mice, 20% BALB/c mice and 10% C57BL/6 mice of the 3× injection group, respectively, whereas 100% lung tumor incidence took place in three mouse strains of the 10× injection group. In the 10× injection group, urethane induced lasting glycolytic stress of lung with an increase in lactate, monocarboxylate transporter 1 (MCT-1), reactive oxygen species(ROS) and 7,8-dihydro-8-oxo-29-deoxyguanosine (8-OHdG) and a decrease in pyruvate dehydrogenase (PDH) and cytochrome C oxidase (COX). In the 3× injection group, urethane also promoted lung glycolytic stress at the end of urethane injection but it lasted no more than 7 days besides in lung tumor-bearing mice. Metformin as a glycolytic enhancer promoted urethane carcinogenic efficacy in the 3× injection group, whereas 2-deoxy-glucose (2-DG) as a glycolytic inhibitor decreased urethane carcinogenic efficacy in the 10× injection group. Further, urethane promoted tumor survival in A549 cells by inducing cancer stem-like cellular state. These data suggest that lasting glycolytic stress is sufficient for urethane-induced lung tumorigenesis, and that urethane 10× injection-induced lung cancer can serve as a valuable model for lung tumor biology and tumor prevention.
authors.affiliation: Institute of Pharmacy, Pharmacy College of Henan University, Jinming District, Kaifeng, Henan Province 475004, China.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Oncology, The First Hospital Affiliated to Henan University, Kaifeng, Henan Province 475001, China.
authors.forename: Jiaxiu
authors.initials: J
authors.lastname: Deng
authors.affiliation: Institute of Pharmacy, Pharmacy College of Henan University, Jinming District, Kaifeng, Henan Province 475004, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Cao
authors.affiliation: Institute of Pharmacy, Pharmacy College of Henan University, Jinming District, Kaifeng, Henan Province 475004, China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Institute of Pharmacy, Pharmacy College of Henan University, Jinming District, Kaifeng, Henan Province 475004, China.
authors.forename: Yaqiu
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Institute of Pharmacy, Pharmacy College of Henan University, Jinming District, Kaifeng, Henan Province 475004, China.
authors.forename: Shengnan
authors.initials: S
authors.lastname: Geng
authors.affiliation: Institute of Pharmacy, Pharmacy College of Henan University, Jinming District, Kaifeng, Henan Province 475004, China.
authors.forename: Mingjing
authors.initials: M
authors.lastname: Meng
authors.affiliation: Institute of Pharmacy, Pharmacy College of Henan University, Jinming District, Kaifeng, Henan Province 475004, China.
authors.forename: Haihong
authors.initials: H
authors.lastname: Lin
authors.affiliation: Department of Oncology, The First Hospital Affiliated to Henan University, Kaifeng, Henan Province 475001, China. Electronic address: dyj9062@163.com.
authors.forename: Yongjian
authors.initials: Y
authors.lastname: Duan
authors.affiliation: Institute of Pharmacy, Pharmacy College of Henan University, Jinming District, Kaifeng, Henan Province 475004, China. Electronic address: 724200@henu.edu.cn.
authors.forename: Gangjun
authors.initials: G
authors.lastname: Du
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000139:chemically induced / Q000473:pathology*; D002273:Carcinogens / Q000633:toxicity; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D003847:Deoxyglucose / Q000494:pharmacology; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000139:chemically induced / Q000473:pathology; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008175:Lung Neoplasms / Q000139:chemically induced / Q000473:pathology*; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects*; D027981:Symporters / Q000378:metabolism; D014520:Urethane / Q000633:toxicity*; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D002273:Carcinogens; D003847:Deoxyglucose; D003576:Electron Transport Complex IV; D019344:Lactic Acid; D008687:Metformin; D027501:Monocarboxylic Acid Transporters; D009097:Multienzyme Complexes; D009247:NADH, NADPH Oxidoreductases; D019289:Pyruvic Acid; D017382:Reactive Oxygen Species; D027981:Symporters; D014520:Urethane; D000099233:Monocarboxylate Transport Protein 1; C023107:NADH oxidase
keywords: Cancer stem cells; Carcinogenesis; Glycolytic stress; Urethane