Abstract
Genistein is a major isoflavonoid in dietary soybean, commonly consumed in Asia. Genistein exerts inhibitory effects on the proliferation of various cancer cells and plays an important role in cancer prevention. However, the molecular and cellular mechanisms of genistein on human ovarian cancer cells are still little known. We show that exposure of human ovarian cancer HO-8910 cells to genistein induces DNA damage, and triggers G2/M phase arrest and apoptosis. Furthermore, we also found that checkpoint proteins ATM and ATR are phosphorylated and activated in the cells treated with genistein. It is also shown that genistein increases the phosphorylation and activation of Chk1 and Chk2, which results in the phosphorylation and inactivation of phosphatases Cdc25C and Cdc25A, and thereby the phosphorylation and inactivation of Cdc2 which arrests cells in G2/M phase. Moreover, genistein enhances the phosphorylation and activation of p53, while decreases the ratio of Bcl-2/Bax and Bcl-xL/Bax and the level of phosphorylated Akt, which result in cells undergoing apoptosis. These results demonstrate that genistein-activated ATM-Chk2-Cdc25 and ATR-Chk1-Cdc25 DNA damage checkpoint pathways can arrest ovarian cancer cells in G2/M phase, and induce apoptosis while the cellular DNA damage is too serious to be repaired. Thus, the antiproliferative, DNA damage-inducing and pro-apoptotic activities of genistein are probably responsible for its genotoxic effects on human ovarian cancer HO-8910 cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anticarcinogenic Agents / pharmacology*
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Apoptosis / drug effects*
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Apoptosis / genetics
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Ataxia Telangiectasia Mutated Proteins
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BRCA1 Protein / metabolism
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CDC2 Protein Kinase
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Cell Cycle / drug effects*
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Cell Cycle / genetics
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Checkpoint Kinase 1
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Checkpoint Kinase 2
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Cyclin B / metabolism
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Cyclin-Dependent Kinases
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DNA Damage / drug effects*
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DNA-Binding Proteins / metabolism
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Female
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Genistein / pharmacology*
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Humans
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Ovarian Neoplasms / drug therapy*
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Ovarian Neoplasms / genetics*
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Ovarian Neoplasms / metabolism
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Ovarian Neoplasms / pathology*
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Phosphorylation
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Protein Kinases / metabolism
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Protein Serine-Threonine Kinases / metabolism
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Signal Transduction / drug effects*
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Signal Transduction / genetics
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Tumor Suppressor Proteins / metabolism
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bcl-2-Associated X Protein / metabolism
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bcl-X Protein / metabolism
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cdc25 Phosphatases / metabolism
Substances
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Anticarcinogenic Agents
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BRCA1 Protein
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Cell Cycle Proteins
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Cyclin B
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DNA-Binding Proteins
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Rad17 protein, human
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Tumor Suppressor Proteins
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bcl-2-Associated X Protein
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bcl-X Protein
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Genistein
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Protein Kinases
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Checkpoint Kinase 2
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ATM protein, human
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ATR protein, human
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Ataxia Telangiectasia Mutated Proteins
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CHEK1 protein, human
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CHEK2 protein, human
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Checkpoint Kinase 1
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Protein Serine-Threonine Kinases
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CDC2 Protein Kinase
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CDK1 protein, human
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Cyclin-Dependent Kinases
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CDC25A protein, human
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CDC25C protein, human
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cdc25 Phosphatases