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Continuous activation of Nrf2 and its target antioxidant enzymes leads to arsenite-induced malignant transformation of human bronchial epithelial cells.
Toxicol Appl Pharmacol. 2015 Dec 01; 289(2):231-9.TA

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+Show Affiliations

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, 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.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, 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, 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, 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, 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, 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, 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, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou, Jiangsu, People's Republic of China.Laboratory of Environmental Toxicology and Carcinogenesis, School of Pharmacy, Nihon University, Chiba, Japan.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26420645

Citation

Yang, Xu, et al. "Continuous Activation of Nrf2 and Its Target Antioxidant Enzymes Leads to Arsenite-induced Malignant Transformation of Human Bronchial Epithelial Cells." Toxicology and Applied Pharmacology, vol. 289, no. 2, 2015, pp. 231-9.
Yang X, Wang D, Ma Y, et al. Continuous activation of Nrf2 and its target antioxidant enzymes leads to arsenite-induced malignant transformation of human bronchial epithelial cells. Toxicol Appl Pharmacol. 2015;289(2):231-9.
Yang, X., Wang, D., Ma, Y., Xu, X., Zhu, Z., Wang, X., Deng, H., Li, C., Chen, M., Tong, J., Yamanaka, K., & An, Y. (2015). Continuous activation of Nrf2 and its target antioxidant enzymes leads to arsenite-induced malignant transformation of human bronchial epithelial cells. Toxicology and Applied Pharmacology, 289(2), 231-9. https://doi.org/10.1016/j.taap.2015.09.020
Yang X, et al. Continuous Activation of Nrf2 and Its Target Antioxidant Enzymes Leads to Arsenite-induced Malignant Transformation of Human Bronchial Epithelial Cells. Toxicol Appl Pharmacol. 2015 Dec 1;289(2):231-9. PubMed PMID: 26420645.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Continuous activation of Nrf2 and its target antioxidant enzymes leads to arsenite-induced malignant transformation of human bronchial epithelial cells. AU - Yang,Xu, AU - Wang,Dapeng, AU - Ma,Yuan, AU - Xu,Xiguo, AU - Zhu,Zhen, AU - Wang,Xiaojuan, AU - Deng,Hanyi, AU - Li,Chunchun, AU - Chen,Min, AU - Tong,Jian, AU - Yamanaka,Kenzo, AU - An,Yan, Y1 - 2015/09/28/ PY - 2015/03/02/received PY - 2015/09/22/revised PY - 2015/09/25/accepted PY - 2015/10/1/entrez PY - 2015/10/1/pubmed PY - 2016/3/10/medline KW - Antioxidant response KW - Arsenite KW - Carcinogenesis KW - HBE cells KW - Nrf2 SP - 231 EP - 9 JF - Toxicology and applied pharmacology JO - Toxicol Appl Pharmacol VL - 289 IS - 2 N2 - 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. SN - 1096-0333 UR - https://www.unboundmedicine.com/medline/citation/26420645/Continuous_activation_of_Nrf2_and_its_target_antioxidant_enzymes_leads_to_arsenite_induced_malignant_transformation_of_human_bronchial_epithelial_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041-008X(15)30094-6 DB - PRIME DP - Unbound Medicine ER -