Chronic low dose arsenic exposure preferentially perturbs mitotic phase of the cell cycle

Suthakar Ganapathy,Tianqi Yu,Alexandros Makriyannis,Rui Xiong,Changyan Chen,Jian Liu

doi:10.18632/genesandcancer.185

Abstract

Environmental pollution is a big challenge for human survival. Arsenic compounds are well-known biohazard, the exposure of which is closely linked to onsets of various human diseases, particularly cancers. Upon chronically exposing to arsenic compounds, genomic integrity is often disrupted, leading to tumor development. However, the underlying mechanisms by which chronic, low dose arsenic exposure targets genetic stability to initiate carcinogenesis still remain not fully understood. In this study, human lung epithelial BEAS-2B cells and keratinocytes were treated with 0.5 μM of sodium arsenite for one month (designated as BEAS-2B-SA cells or keratinocytes-SA), and its effect on cell cycle responses was analyzed. After being arrested in mitotic phase of the cell cycle by nocodazole treatment, BEAS-2B-SA cells or keratinocytes-SA were delayed to enter next cytokinesis. The lagging exit of the cells from mitosis was accompanied by a sustained Plk1 phosphorylation, which led to a persistent activation of the mitotic regulators BubR1 and Cdc27. As the result, cyclin B1 (clnB1) degradation was attenuated. BEAS-2B-SA cells or keratinocytes-SA also expressed a constitutively active Akt. The cytogenetic analysis showed an increased numbers of aneuploidy in these cells. The suppression of Akt reversed the aberrant expressions of the mitotic regulators, delay of mitotic exit as well as chromosomal aberrations. Our findings suggest that a long-term exposure to low dose sodium arsenite aberrantly retains the catenation of mitosis, which facilitates establishing genetic instability and predisposes the cells to tumorigenesis.

Highlights

Arsenic compounds are toxic metalloids and exist in polluted water or air, especially in mining or industry areas, exposures of which are serious risks to human health [1, 2]
Low doses of sodium arsente treatment delay prolong cells to exit from mitosis Studies showed that transient, low doses of arsenic treatment appeared to be beneficial for treatments of certain types of cancer, which could induce metabolic changes and inactivating p53 to avoid extensive normal tissue damages surrounding tumor lesions [10, 11, 18, 40]
The results clearly suggested that Polo-like kinase 1 (Plk1) in BEAS2B-SA cells and keratinocytes-SA functions upstream of BubR1, Cdc27 or cyclin B1 (clnB1) and they act in a hierarchy order to perturb the mitotic phase restriction

Summary

Introduction

Arsenic compounds are toxic metalloids and exist in polluted water or air, especially in mining or industry areas, exposures of which are serious risks to human health [1, 2]. It has been reported that transient low dose arsenic treatment had the protective effect of normal tissues against damages caused by radiation- or chemo-therapy, which was through the metabolic switch from mitochondrial respiration to aerobic glycolysis [18, 19]. Despite these findings, the underlying mechanisms by which arsenic promotes tumorigenesis remain not fully understood. Because environmental arsenic pollution affects a large number of human beings worldwide, there is an urgent need for identifying intracellular targets of arsenic in its carcinogenic action, which will help developing new strategies for preventing or treating the diseases caused by the exposure to this metalloid toxin

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Results

Conclusion