Genistein induces G2/M cell cycle arrest and apoptosis of human ovarian cancer cells via activation of DNA damage checkpoint pathways
Genistein induces G2/M cell cycle arrest and apoptosis of human ovarian cancer cells via activation of DNA damage checkpoint pathways
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金雀异黄素通过激活 DNA 损伤检查点途径诱导人卵巢癌细胞 G2/M 细胞周期停滞和凋亡
DOI：
10.1016/j.cellbi.2009.08.011
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发表时间：
2009-12-01
影响因子：
3.9
通讯作者：
Bao, Shideng
中科院分区：
文献类型：
--
作者：
Ouyang, Gaoliang;Yao, Luming;Bao, Shideng
染料木黄酮是亚洲人普遍食用的大豆中的主要生物碱。染料木黄酮对多种癌细胞的增殖具有抑制作用，在癌症预防中起重要作用。然而，染料木黄酮对人卵巢癌细胞作用的分子和细胞机制仍知之甚少。我们发现，金雀异黄素暴露于人卵巢癌HO-8910细胞诱导DNA损伤，并触发G2/M期阻滞和凋亡。此外，我们还发现，检查点蛋白ATM和ATR磷酸化和激活的细胞与染料木素处理。研究还表明，染料木黄酮增加Chk 1和Chk 2的磷酸化和激活，导致磷酸酶Cdc 25 C和Cdc 25 A的磷酸化和失活，从而导致Cdc 2的磷酸化和失活，使细胞停滞在G2/M期。此外，genistein还可增强p53的磷酸化和激活，降低Bcl-2/Bax和Bcl-xL/Bax比值，降低Akt磷酸化水平，从而导致细胞凋亡。这些结果表明，染料木素激活ATM-Chk 2-Cdc 25和ATR-Chk 1-Cdc 25 DNA损伤检查点通路可使卵巢癌细胞阻滞于G2/M期，并在细胞DNA损伤严重无法修复时诱导细胞凋亡。因此，染料木黄酮的抗增殖，DNA损伤诱导和促凋亡活性可能是负责其对人卵巢癌HO-8910细胞的遗传毒性作用。(C)2009年国际细胞生物学联合会。由爱思唯尔有限公司出版。保留所有权利。
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. (C) 2009 International Federation for Cell Biology. Published by Elsevier Ltd. All rights reserved.