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Arsenic is a toxic environmental contaminant. Long-term exposure to arsenic through drinking water induces human cancers. However, it is as yet uncertain about the mechanisms of arsenic induced carcinogenesis. Although the effects of low-dose arsenicals on proliferation and cell cycle have been revealed by short time exposure, the evidences for long-term exposure were seldom reported. The detailed mechanism has been unclear and supplemented constantly. In the present study, we used normal human keratinocytes (HaCat) to study the effects of long-term, low-dose sodium arsenite (NaAsO 2 ) exposure on cell proliferation with emphasis on the Akt regulated cell cycle signaling pathways. Treatment of NaAsO 2  resulted in increased cell proliferation and promotion of cell cycle progression from G1 to S/G2M phase, both of which could be attenuated by MK2206, a highly selective inhibitor of Akt. Along with the increased expression of phospho-Akt ( p -Akt, Ser 473), increased expression of  p -GSK-3β (Ser 9),  p -p21 (Thr 145),  p -p27 (Thr 157) and total cyclin D1, and decreased expression of  p -cyclin D1 (Thr 286), p21 and p27 were also found in the NaAsO 2  exposed cells. Treatment of MK2206 markedly reversed the expression of all of the above proteins. Our findings indicated that the phosphorylated activation of Akt played a role in the proliferation of HaCat cells upon long-term, low-dose NaAsO 2  exposure through the phosphorylative regulation of its downstream cell cycle regulating factors of GSK-3β/cyclin D1, p21 and p27, which could induce the promotion of cell cycle progression from G1 to S/G2M phase.

frontiers in pharmacology

Akt Regulated Phosphorylation of GSK-3β/Cyclin D1, p21 and p27 Contributes to Cell Proliferation Through Cell Cycle Progression From G1 to S/G2M Phase in Low-Dose Arsenite Exposed HaCat Cells