Repeated radon exposure induced epithelial-mesenchymal transition-like transformation via disruption of p53-dependent mitochondrial function

Author:

Shan Shan1,Chen Xiaoyu1,Wang Aiqing2,Yan Weici1,Wu Qianqian1,Wan Jianmei2,Hong Chengjiao2,Wang Yarong2,Tong Jian1,Tian Hailin1ORCID,Xin Lili134ORCID

Affiliation:

1. School of Public Health, Suzhou Medical College of Soochow University , 199 Renai Road, Suzhou, Jiangsu 215123, China

2. Department of Experimental Center, Suzhou Medical College of Soochow University , 199 Renai Road, Suzhou, Jiangsu 215123, China

3. School of Public Health , Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, MOE Key Laboratory of Geriatric Diseases and Immunology, , 199 Renai Road, Suzhou, Jiangsu 215123, China

4. Suzhou Medical College of Soochow University , Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, MOE Key Laboratory of Geriatric Diseases and Immunology, , 199 Renai Road, Suzhou, Jiangsu 215123, China

Abstract

Abstract Backgrouds As a human carcinogen, radon and its progeny are the second most important risk factor for lung cancer after smoking. The tumor suppressor gene, p53, is reported to play an important role in the maintenance of mitochondrial function. In this work, we investigated the association between p53 and p53-responsive signaling pathways and radon-induced carcinogenesis. Methods After repeated radon exposure, the malignant characteristics, cell cycle arrest, cell apoptotic rate, adenosine triphosphate (ATP) content, reactive oxygen species (ROS) level, mitochondrial DNA (mtDNA) copy number as well as indicative biomarkers involved in mitochondrial energy metabolism were evaluated in BEAS-2B cells or BALB-c mouse lung tissue. Results Radon exposure induced epithelial-mesenchymal transition (EMT)-like transformation in BEAS-2B cells, as indicated by increased cell proliferation and migration. Additional mitochondrial alterations, including decreased ATP content, increased ROS levels, mtDNA copy numbers, cell apoptosis, and G2/M cell cycle arrest were observed. Radon exposure caused an energy generation shift from aerobic respiration to glycolysis as reflected by increased expression of TIGAR and p53R2 proteins and decreased expression of SCO2 protein in BEAS-2B cells, and increased expression of p53, SCO2 and TIGAR proteins in mouse lung tissue, respectively. The effects of p53 deficiency on the prevention of mitochondrial dysfunction suggested a protective role of p53 in radon-induced malignant-like features in BEAS-2B cells. Conclusions Repeated radon exposure induced EMT-like transformation in BEAS-2B cells via disruption of mitochondrial function. Activation of p53 and p53-responsive signaling pathways in BEAS-2B cells and BALB-c mice may confer a protective mechanism for radon-induced lung injury.

Funder

National Natural Science Foundation of China

Publisher

Oxford University Press (OUP)

Subject

Health, Toxicology and Mutagenesis,Toxicology

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