Genistein induces G2/M cell cycle arrest and apoptosis of human ovarian cancer cells via activation of DNA damage checkpoint pathways

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.

The oncogenic phosphatase PPM1D confers cisplatin resistance in ovarian carcinoma cells by attenuating checkpoint kinase 1 and p53 activation

“…Ser 345 phosphorylation is an essential phosphorylation site for Chk1 nuclear localization and retention. If the DNA damage is too serious to be repaired, ATR activates p53 through phosphorylation of Ser 15 and Ser 20 directly and indirectly through Chk1 (Graves et al, 2000;Capasso et al, 2002;Jiang et al, 2003;Yazlovitskaya and Persons, 2003;Qu et al, 2005;Ouyang et al, 2009;Rong et al, 2010). It has also been established that the p53-responsive phosphatase PPM1D modulates the action of ATR by direct dephosphorylation of phospho-Ser 15 of p53 and phosphoSer 345 of Chk1 (Choi et al, 2000;Lu et al, 2004;Lu et al, 2005;Yamaguchi et al, 2007;Lu et al, 2008).…”

Modulation of inflammatory signaling pathways by phytochemicals in ovarian cancer

“…Genistein has been shown to inhibit cell proliferation, cause cell cycle arrest at G2/M phase, and induce apoptosis in ovarian cancer cells [12,44]. In addition, genistein treatment also induces autophagic cell death in ovarian cancer cells, which may contribute to its potential to overcome chemoresistance developed from an altered apoptotic signaling pathway [20].…”

Fabrication of genistein-loaded biodegradable TPGS-b-PCL nanoparticles for improved therapeutic effects in cervical cancer cells

“…5,6 Recent studies have indicated that genistein could inhibit tumor cell growth and proliferation, arrest cell cycle at G2/M phase, suppress tumor migration, invasion, and angiogenesis, and induce apoptosis and autophagocytosis. [7][8][9][10][11] However, the clinical use of genistein for cancer therapy was hindered by its poor water solubility and oral bioavailability. The emerging applications of nanotechnology-based cancer therapy provide a potent platform to improve poor water solubility and bioavailability of hydrophobic antitumor agents.…”