Cyclin D1 induction through IκB kinase β/nuclear factor-κB pathway is responsible for arsenite-induced increased cell cycle G1-S phase transition in human keratinocytes

Environmental and occupational exposure to arsenite is associated with an increased risk of human cancers, including skin, urinary bladder, and respiratory tract cancers. Although much evidence suggests that alterations in cell cycle machinery are implicated in the carcinogenic effect of arsenite, the molecular mechanisms underlying the cell cycle alterations are largely unknown. In the present study, we observed that exposure of human keratinocyte HaCat cells to arsenite resulted in the promotion of cell cycle progression, especially G(1)-S transition. Further studies found that arsenite exposure was able to induce cyclin D-1 expression. The induction of cyclin D-1 by arsenite required nuclear factor-kappa B (NF-kappa B) activation, because the inhibition of I kappa B phosphorylation by overexpression of the dominant-negative mutant, IKK beta-KM, impaired arsenite-induced cyclin D1 expression and G(1)-S transition. The requirement of I kappa B kinase (IKK beta) for cyclin D1 induction was further confirmed by the findings that arsenite-induced cyclin D1 expression was totally blocked in IKK beta knockout (IKK beta(-/-)) mouse embryo fibroblasts. In addition, knockdown of cyclin D1 expression using cyclin D1-specific small interference RNA significantly blocked arsenite-induced cell cycle progression in HaCat cells. Taken together, our results show that arsenite-induced cell cycle from G(1) to S phase transition is through IKK beta/NF-kappa B/cyclin D1-dependent pathway.