US EPA

1337383 

Journal Article 

Low concentration of arsenic-induced aberrant mitosis in keratinocytes through E2F1 transcriptionally regulated Aurora-A 

Wu, C-H; Tseng, Y-S; Kao, Y-T; Sheu, H-M; Liu, H-S 

2013 

1 

Toxicological Sciences
ISSN: 1096-6080
EISSN: 1096-0929 

132 

1 

43-52 

English 

23174854 

10.1093/toxsci/kfs322 

WOS:000315434300005 

Chronic exposure to low concentration arsenic promotes cell proliferation and carcinogenesis both in vitro and in vivo. Centrosome amplification, the major cause of chromosome instability, occurs frequently in cancers. Aurora-A is a mitotic kinase and causes centrosome amplification and chromosome instability when overexpressed. Our previous study revealed that low concentration arsenic induces Aurora-A overexpression in immortalized bladder cells. In this study, we hypothesized that low concentration arsenic induces aberrant mitosis in keratinocytes due to Aurora-A overexpression. The specimen of Bowen's disease (BD) and squamous cell carcinoma obtained from arseniasis-endemic areas in Taiwan showed Aurora-A overexpression. The mRNA/protein levels and kinase activity of Aurora-A were increased in immortalized keratinocyte HaCaT cells after arsenic treatment at low concentration (<1μM). Aberrant spindles, multiple centrosomes and multinucleated cells were detected under fluorescent microscopy in HaCaT cells after arsenic treatment. These findings were associated with increased expression of Aurora-A. We further revealed that Aurora-A was regulated by arsenic-induced transcriptional factor E2F1 as demonstrated by chromosome immunoprecipitation, promoter activity and small interfering RNA assays. Finally, in arsenic-treated HaCaT cells and in BD, a significant increase of dysfunctional p53 was found, and this event correlated with the increase expression of Aurora-A. Altogether, our data suggest that low concentration of arsenic induces activation of E2F1-Aurora-A axis and results in aberrant mitosis of keratinocytes. Overexpression of Aurora-A and dysfunctional p53 may act synergistically to trigger skin tumor formation. Our findings suggest that Aurora-A may be a potential target for the prevention and treatment of arsenic-related cancers. 

Aurora-A; arsenic; keratinocyte; mitosis