Genistein induces G2/M cell cycle arrest via stable activation of ERK1/2 pathway in MDA-MB-231 breast cancer cells.
Genistein is an isoflavonoid present in soybeans that exhibits anti-carcinogenic effect. Several studies have shown that genistein can trigger G2/M cell cycle arrest and inhibit cell growth in human breast cancer cells. In the present study, we assessed the role of MEK-ERK cascade in regulation of genistein-mediated G2/M cell cycle arrest in the hormone-independent cell line MDA-MB-231. Flow cytometric analysis showed that treatment of MDA-MB-231 cells with genistein induced a concentration-dependent accumulation of cells in the G2/M phase of the cell cycle, with a parallel depletion of the percentage of cells in G0/G1. Genistein-mediated G2/M arrest was associated with a decrease in the protein levels of Cdk1, cyclinB1, and Cdc25C as determined by Western blot analysis. Genistein induced a slow and stable activation of phosphorylated ERK1/2 in a concentration- and time-dependent manner in MDA-MB-231 cells. MEK1/2-specific inhibitor PD98059 blocked genistein-induced activation of ERK1/2 and markedly attenuated genistein-induced G2/M arrest. Furthermore, genistein induced the expression of Ras and Raf-1 protein. Genistein also up-regulated steady-state levels of both c-Jun and c-Fos. PD98059 did not depress genistein-induced up-regulation of Ras and Raf-1 protein. However, it markedly blocked genistein-induced up-regulation of c-Jun and c-Fos. These results suggest that the Ras/MAPK/AP-1 signal pathway may be involved in genistein-induced G2/M cell cycle arrest in MDA-MB-231 breast cancer cells.
Li
Zhong
Z
The Key Laboratory of Reproductive Medicine of Jiangsu Province, Institute of Toxicology, Nanjing Medical University, NO. 140 Hanzhong Rd, Jiangsu, Nanjing 210029, China. uiuclz@126.com
Li
Jing
J
Mo
Baoqing
B
Hu
Chunyan
C
Liu
Huaqing
H
Qi
Hong
H
Wang
Xinru
X
Xu
Jida
J
D002453:Cell Cycle; D002455:Cell Division; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005419:Flavonoids / Q000494:pharmacology; D005434:Flow Cytometry / Q000379:methods; D016195:G2 Phase; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism
D005419:Flavonoids; D047428:Protein Kinase Inhibitors; D019833:Genistein; D019908:Proto-Oncogene Proteins c-raf; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one