Sodium Arsenite Induces Bronchial Epithelial Cell Cancer With Mitochondrial Dysfunction by Affecting Cell Cycle

Background: Arsenide, a kind of pollution widely existing in the environment, and the mechanism of occurrence and development of lung cancer leading by long-term arsenic exposure still needs further research up to present. We investigated how high and low doses of arsenic induce human bronchial epithelial cell transformation and the molecular mechanisms involvedMethods: After exposing human bronchial epithelial cells(Beas-2B) to different doses of sodium arsenite for 24 h, RNA-seq analysis was performed to detect arsenic-regulated genes; for cell viability and status and for cell cycle changes and mitochondrial function; long-term exposure to 1μM sodium arsenite after 20 consecutive passages for cell cycle changes and mitochondrial function.Results: In the study, human bronchial epithelial cells were exposed to varying high-dose sodium arsenite in short term or treated with low dose in a long term, and the data showed that both short and long terms treatment promoted G1/S transition of Beas-2B cells, inducing significant increases of expression of AKAP95, cyclin D1, cyclin D2 and cyclin E1. However, silencing AKAP95 by treating cells with siAKAP95 showed a protective function that inhibited G1/S transition, suggesting that regulatory mechanism of AKAP95 on cell cycle during cell malignant transformation induced by sodium arsenite. In addition, we also noticed some mitochondrial dysfunctions occurred during sodium arsenite exposure, including the disappearance of mitochondrial double membrane structure, the formation of vacuole structure, the decrease of mitochondrial membrane potential, the change of expression levels of mitochondrial related proteins Tim22, Tim23, Tom40 and OPA1, the release of lactate dehydrogenase (LDH) and the decrease of reduced glutathione.Beas-2B cells, which exposed to low-dose sodium arsenite for a long term, were subcultured for 20 generations, and it was found that the exposure time was positively proportional to the growth and migration rate of cells. The exposed cells were used in tumor bearing transplantation experiment (mice), and results showed that the longer the exposure time, the faster the tumor volume growth rate of As-Beas-2B cells. Tumor tissues were taken out for HE staining, and it was found that the cell morphology changed and the volume increasedConclusion: high and low doses of sodium arsenite induced malignant transformation of human bronchial epithelial cells by promoting G1/S turnover through AKAP95 with associated cyclins, accompanied by the development of mitochondrial dysfunction.