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Cancer Epidemiology Biomarkers & Prevention

Year: 2009  |  Volume: 18  |  Issue: 6  |  Page No.: 1720 - 1729

Effects of Nickel on Cyclin Expression, Cell Cycle Progression and Cell Proliferation in Human Pulmonary Cells

J Ding, G He, W Gong, W Wen, W Sun, B Ning, S Huang, K Wu, C Huang, M Wu, W Xie and H. Wang

Abstract

Frequent exposure to nickel compounds has been considered as one of the potential causes of human lung cancer. However, the molecular mechanism of nickel-induced lung carcinogenesis remains obscure. In the current study, slight S-phase increase, significant G2/M cell cycle arrest, and proliferation blockage were observed in human bronchial epithelial cells (Beas-2B) upon nickel exposure. Moreover, the induction of cyclin D1 and cyclin E by nickel was shown for the first time in human pulmonary cells, which may be involved in nickel-triggered G1/S transition and cell transformation. In addition, we verified that hypoxia-inducible factor-1, an important transcription factor of nickel response, was not required for the cyclin D1 or cyclin E induction. The role of p53 in nickel-induced G2/M arrest was excluded, respecting that its protein level, ser15 phosphorylation, and transcriptional activity were not changed in nickel response. Further study revealed that cyclin A was not activated in nickel response, and cyclin B1, which not only promotes G2/M transition but also prevents M-phase exit of cells if not degraded in time, was up-regulated by nickel through a manner independent of hypoxia-inducible factor. More importantly, our results verified that overexpressed cyclin B1, veiling the effect of cyclin D1 or cyclin E, mediated nickel-caused M-phase blockage and cell growth inhibition, which may render pulmonary cells more sensitive to DNA damage and facilitates cancer initiation. These results will not only deepen our understanding of the molecular mechanism involved in nickel carcinogenecity, but also lead to the further study on chemoprevention of nickel-associated human cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(6):1720–9)

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