Journal
WORLD JOURNAL OF GASTROENTEROLOGY
Volume 14, Issue 25, Pages 3982-3989Publisher
BAISHIDENG PUBLISHING GROUP INC
DOI: 10.3748/wjg.14.3982
Keywords
lithium; esophageal cancer; cell cycle; glycogen synthase kinase 3 beta
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AIM: To investigate the effect of lithium on proliferation of esophageal cancer (EC) cells and its preliminary mechanisms. METHODS: Eca-109 cells were treated with lithium chloride, a highly selective inhibitor of glycogen synthase kinase 3 beta (GSK-3 beta), at different concentrations (2-30 mmol/L) and time points (0, 2, 4, 6 and 24 h). Cell proliferative ability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, and cell cycle distribution was examined by flow cytometry. Expressions of p-GSK-3 beta, beta-catenin, cyclin B1, cdc2 and cyclin D1 protein were detected by Western blotting, and the subcellular localization of beta-catenin was determined by immunofluorescence. The mRNA level of cyclin 81 was detected by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Lithium could inhibit the proliferation of Eca-109 cells. Lithium at a concentration of 20 mmol/L lithium for 24 h produced obvious changes in the distribution of cell cycle, and increased the number of cells in G(2)/M phase (P < 0.05 vs control group). Western blotting showed that lithium inhibited GSK-3 beta by Ser-9 phosphorylation and stabilized free beta-catenin in the cytoplasm. Immunofluorescence further confirmed that free beta-catenin actively translocated to the nucleus. Moreover, lithium slightly elevated cyclin D1 protein expression, whereas lowered the cyclin B1 expression after 24 h lithium exposure and no obvious change was observed for cdc2 protein. CONCLUSION: Lithium can inhibit the proliferation of human esophageal cancer cell line Eca-109 by inducing a G(2)/M cell cycle arrest, which is mainly mediated through the inhibition of lithium-sensitive molecule, GSK-3 beta, and reduction of cyclin B1 expression. (C) 2008 The WJG Press. All rights reserved.
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