Lithium suppresses cell proliferation by interrupting E2F–DNA interaction and subsequently reducing S–phase gene expression in prostate cancer

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Abstract
BACKGROUND Lithium is an existing drug for bipolar disorder and its uptake was recently linked to reduced tumor incidence compared to the general population. The major target of lithium action is glycogen synthase kinase 3 (GSK-3). Since GSK-3 expression and activation are associated with prostate cancer progression, the anti-cancer potential of lithium on prostate cancer was investigated in this study. METHODS Multiple prostate cancer cell lines were treated with lithium chloride (LiCl). Cell proliferation and cell cycle distribution were analysed. DNA replication was determined using BrdU labeling assay. Genome-wide screening of gene expression was performed using cDNA microarray assay. GSK-3β gene-specific silencing was conducted using small interferencing RNA (siRNA) transfection. E2 factor (E2F) transactivation was evaluated using reporter gene assay and E2F–DNA interaction was determined with chromatin-immunoprecipitation assay (ChIP). RESULTS LiCl significantly inhibited cell proliferation, which was associated with reduced DNA replication and S-phase cell cycle arrest. LiCl significantly decreased the expression of multiple DNA replication-related genes, including cell division cycle 6 (cdc6), cyclin A, cyclin E, and cdc25C, which are regulated by E2F factor during cell cycle. A novel GSK-3-specific inhibitor TDZD-8 and GSK-3β siRNA also suppressed the expression of these E2F target genes, indicating that LiCl-induced anti-cancer effect was associated with GSK-3β inhibition. Furthermore, LiCl suppressed E2F transactivation by interrupting the interaction of E2F1 factor with its target gene promoter. CONCLUSIONS These data indicated that LiCl suppresses cancer cell proliferation by disrupting E2F–DNA interaction and subsequent E2F-mediated gene expression in prostate cancer. Prostate 67: 976–988, 2007.