title: Calmodulin as a potential target by which berberine induces cell cycle arrest in human hepatoma Bel7402 cells.
abstract: Berberine is an isoquinoline alkaloid that has drawn extensive attention because it possesses various biological activities. Several mechanisms have been proposed to interpret the anticancer activity of berberine. However, these explanations are mostly based on its downstream-regulated genes or proteins; information on the direct target proteins that mediate the antiproliferative action of berberine remains unclear. In this study, a computational pipeline based on a ligand-protein inverse docking program and mining of the 'Connectivity MAP' data was adopted to explore the potential target proteins for berberine. The results showed that four proteins, that is calmodulin, cytochrome P450 3A4, sex hormone-binding globulin, and carbonic anhydrase II, were suggested to be the potential targets of berberine. The anticalmodulin property of berberine was demonstrated with an in vitro phosphodiesterase activity assay. Flow cytometric analysis found that G1 cell cycle arrest induced by berberine in Bel7402 cells was enhanced by cotreatment with calmodulin inhibitors. Western blotting results indicated that berberine treatment decreased phosphorylation of calmodulin kinase II and blocked subsequent MEK1 activation as well as p27 protein degradation. These results suggested that calmodulin might play crucial roles in berberine-induced cell cycle arrest in cancer cells.
authors: School of Life Sciences and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, China.
authors: Chao
authors: C
authors: Ma
authors: Kailin
authors: K
authors: Tang
authors: Qi
authors: Q
authors: Liu
authors: Ruixin
authors: R
authors: Zhu
authors: Zhiwei
authors: Z
authors: Cao
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000633:toxicity; D001599:Berberine / Q000737:chemistry* / Q000633:toxicity; D001665:Binding Sites; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002147:Calmodulin / Q000737:chemistry* / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D062105:Molecular Docking Simulation; D010766:Phosphorylation; D017434:Protein Structure, Tertiary
chemical_list: D000970:Antineoplastic Agents; D002147:Calmodulin; D001599:Berberine; D050760:Cyclin-Dependent Kinase Inhibitor p27; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D048369:MAP Kinase Kinase 1