Journal Article

Low Concentration of Arsenic-Induced Aberrant Mitosis in Keratinocytes Through E2F1 Transcriptionally Regulated Aurora-A

Chin-Han Wu, Ya-Shih Tseng, Yu-Ting Kao, Hamm-Ming Sheu and Hsiao-Sheng Liu

in Toxicological Sciences

Volume 132, issue 1, pages 43-52
Published in print March 2013 | ISSN: 1096-6080
Published online November 2012 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfs322
Low Concentration of Arsenic-Induced Aberrant Mitosis in Keratinocytes Through E2F1 Transcriptionally Regulated Aurora-A

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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 in 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.

Keywords: Aurora-A; arsenic; keratinocyte; mitosis.

Journal Article.  6153 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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