It is well-known that insoluble
nickel compounds possess much more potent carcinogenic activities as compared with soluble
nickel compounds. Although it is assumed that the different entry and clearance rate are responsible for the difference, the mechanisms underlying the different carcinogenic activities are still not well understood yet. In the present study, we found that exposure to soluble, but not insoluble
nickel compounds, caused a significant inhibition of cell growth and G1/G0 cell cycle arrest, which was concomitant with a marked down-regulation of cylin D1, an essential
nuclear protein for controlling G1/S transition, while both soluble and insoluble
nickel compounds showed similar effects on NFkappaB activation, HIF-1alpha
protein accumulation and
TNF-alpha transcription and CAP43
protein expression at same doses range. The down-regulation of
cyclin D1 is due to protein degradation rather than inhibition of transcription, because the
nickel compounds treatment did not change
cyclin D1 mRNA level, while
MG132, the
proteasome inhibitor, can rescue the degradation of
cyclin D1 caused by soluble
nickel compound. Moreover, the soluble
nickel-induced
cyclin D1 degradation is dependent on its Thr286 residue and requires IKKalpha, but not HIF-1alpha, which are both reported to be involved in
cyclin D1 down-regulation. Taken together, we demonstrate that soluble, but not insoluble
nickel compound, is able to cause
cyclin D1 degradation and a cell growth arrest in an IKKalpha-dependent manner. Given the role of
cyclin D1 and cell proliferation in
carcinogenesis, we anticipate that the different effects of soluble and insoluble
nickel compounds on
cyclin D1 degradation and cell growth arrest may at least partially account for their different carcinogenic activities.