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

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Abstract
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 G1-S transition. Further studies found that arsenite exposure was able to induce cyclin D1 expression. The induction of cyclin D1 by arsenite required nuclear factor-κB (NF-κB) activation, because the inhibition of IκB phosphorylation by overexpression of the dominant-negative mutant, IKKβ-KM, impaired arsenite-induced cyclin D1 expression and G1-S transition. The requirement of IκB kinase β (IKKβ) for cyclin D1 induction was further confirmed by the findings that arsenite-induced cyclin D1 expression was totally blocked in IKKβ knockout (IKKβ−/−) 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 G1 to S phase transition is through IKKβ/NF-κB/cyclin D1–dependent pathway.