Abstract
BackgroundArsenic is a widely distributed metalloid compound that has biphasic effects on cultured cells. In large doses, arsenic can be toxic enough to trigger cell death. In smaller amounts, non-toxic doses may promote cell proliferation and induces carcinogenesis. Aberration of chromosome is frequently detected in epithelial cells and lymphocytes of individuals from arsenic contaminated areas. Overexpression of Aurora-A, a mitotic kinase, results in chromosomal instability and cell transformation. We have reported that low concentration (≦1 μM) of arsenic treatment increases Aurora-A expression in immortalized bladder urothelial E7 cells. However, how arsenic induces carcinogenesis through Aurora-A activation remaining unclear.MethodsBromodeoxyuridine (BrdU) staining, MTT assay, and flow cytometry assay were conducted to determine cell proliferation. Messenger RNA and protein expression levels of Aurora-A were detected by reverse transcriptional-PCR and Western blotting, respectively.Centrosome of cells was observed by immunofluorescent staining. The transcription factor of Aurora-A was investigated by promoter activity, chromosome immunoprecipitation (ChIP), and small interfering RNA (shRNA) assays. Mouse model was utilized to confirm the relationship between arsenic and Aurora-A.ResultsWe reveal that low dosage of arsenic treatment increased cell proliferation is associated with accumulated cell population at S phase. We also detected increased Aurora-A expression at mRNA and protein levels in immortalized bladder urothelial E7 cells exposed to low doses of arsenic. Arsenic-treated cells displayed increased multiple centrosome which is resulted from overexpressed Aurora-A. Furthermore, the transcription factor, E2F1, is responsible for Aurora-A overexpression after arsenic treatment. We further disclosed that Aurora-A expression and cell proliferation were increased in bladder and uterus tissues of the BALB/c mice after long-term arsenic (1 mg/L) exposure for 2 months.ConclusionWe reveal that low dose of arsenic induced cell proliferation is through Aurora-A overexpression, which is transcriptionally regulated by E2F1 both in vitro and in vivo. Our findings disclose a new possibility that arsenic at low concentration activates Aurora-A to induce carcinogenesis.
Highlights
Arsenic is a widely distributed metalloid compound that has biphasic effects on cultured cells
To clarify whether arsenic affects the bladder cancer cells, we dissected the cell population of immortalized bladder urothelial E7 cells at each cell cycle state after low concentration of arsenic (0.5, 0.75 and 1 μM) treatment by PI staining following with flow cytometry analysis
Low dose of arsenic treatment induced Aurora-A overexpression followed by multiple centrosome formation We previously reported that chronic arsenic exposure leads to increased Aurora-A expression in human bladder cancer [19]
Summary
Arsenic is a widely distributed metalloid compound that has biphasic effects on cultured cells. How arsenic induces carcinogenesis through Aurora-A activation remaining unclear. Arsenic in the drinking water correlates with high incidence of bladder, lung, renal, and skin cancers in the areas of endemic BFD [5,6,7,8,9]. The correlation between arsenic exposure and occurrence of bladder cancer has been demonstrated by epidemiological studies [8, 9]. This speculation was supported by setting up the tap-water supply system in these arsenic endemic regions and bladder cancer mortality rate reduced afterword [10]. The duration of arsenic exposure is another parameter involved in the carcinogenesis
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