title: Continuous activation of Nrf2 and its target antioxidant enzymes leads to arsenite-induced malignant transformation of human bronchial epithelial cells.
abstract: Long-term exposure to arsenite leads to human lung cancer, but the underlying mechanisms of carcinogenesis remain obscure. The transcription factor of nuclear factor-erythroid-2 p45-related factor (Nrf2)-mediated antioxidant response represents a critical cellular defense mechanism and protection against various diseases. Paradoxically, emerging data suggest that the constitutive activation of Nrf2 is associated with cancer development, progression and chemotherapy resistance. However, the role of Nrf2 in the occurrence of cancer induced by long-term arsenite exposure remains to be fully understood. By establishing transformed human bronchial epithelial (HBE) cells via chronic low-dose arsenite treatment, we showed that, in acquiring this malignant phenotype, continuous low level of ROS and sustained enhancement of Nrf2 and its target antioxidant enzyme levels were observed in the later-stage of arsenite-induced cell transformation. The downregulation of Keap1 level may be responsible for the over-activation of Nrf2 and its target enzymes. To validate these observations, Nrf2 was knocked down in arsenite-transformed HBE cells by SiRNA transfection, and the levels of Nrf2 and its target antioxidant enzymes, ROS, cell proliferation, migration, and colony formation were determined following these treatments. Results showed that blocked Nrf2 expression significantly reduced Nrf2 and its target antioxidant enzyme levels, restored ROS levels, and eventually suppressed cell proliferation, migration, and colony formation of the transformed cells. In summary, the results of the study strongly suggested that the continuous activation of Nrf2 and its target antioxidant enzymes led to the over-depletion of intracellular ROS levels, which contributed to arsenite-induced HBE cell transformation.
authors.affiliation: Department of Toxicology, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou, Jiangsu, People's Republic of China.
authors.forename: Xu
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Toxicology, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou, Jiangsu, People's Republic of China; Department of Toxicology, School of Public Health, Guizhou Medical University, Guiyang, Guizhou, People's Republic of China.
authors.forename: Dapeng
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Toxicology, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou, Jiangsu, People's Republic of China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Toxicology, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou, Jiangsu, People's Republic of China.
authors.forename: Xiguo
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Toxicology, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou, Jiangsu, People's Republic of China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Toxicology, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou, Jiangsu, People's Republic of China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Toxicology, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou, Jiangsu, People's Republic of China.
authors.forename: Hanyi
authors.initials: H
authors.lastname: Deng
authors.affiliation: Department of Toxicology, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou, Jiangsu, People's Republic of China.
authors.forename: Chunchun
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Toxicology, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou, Jiangsu, People's Republic of China.
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Toxicology, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou, Jiangsu, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Tong
authors.affiliation: Laboratory of Environmental Toxicology and Carcinogenesis, School of Pharmacy, Nihon University, Chiba, Japan.
authors.forename: Kenzo
authors.initials: K
authors.lastname: Yamanaka
authors.affiliation: Department of Toxicology, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou, Jiangsu, People's Republic of China. Electronic address: dranyan@126.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: An
mesh_terms: D000975:Antioxidants / Q000378:metabolism*; D018053:Arsenites / Q000633:toxicity*; D001980:Bronchi / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D002273:Carcinogens / Q000633:toxicity*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008315:Malondialdehyde / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D018384:Oxidative Stress / Q000187:drug effects; D010641:Phenotype; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D017670:Sodium Compounds / Q000633:toxicity*; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: D000975:Antioxidants; D018053:Arsenites; D002273:Carcinogens; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; D017670:Sodium Compounds; C017947:sodium arsenite; D008315:Malondialdehyde; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D013482:Superoxide Dismutase; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human
keywords: Antioxidant response; Arsenite; Carcinogenesis; HBE cells; Nrf2