Abstract
Purpose: Genistein, a soy isoflavone, exhibits a biphasic effect on cells proliferation with some different effects between ER-alpha and ER-beta. The objective of this present study is to determine the modulatory effect based on cell cycle progression under genistein treatment in combination with 17-β estradiol (E2) on CHO-K1 cells. Methods: The effect of genistein 0.1-100 µM on cells proliferation was examined by MTT assay. The modulation of genistein and estradiol (E2) on cell cycle and apoptosis were observed by using flowcytometry with PI and PI/AnnexinV staining, respectively. Moreover, the effect of genistein and E2 on senescence cells, and ROS level were determined by senescence-associated β-galactosidase (SA β-gal) staining and by using flowcytometry with 2’, 7’–dichlorofluorescin diacetate (DCFDA) staining, respectively. The expression level of the cell cycle and senescence protein markers were observed by immunoblotting. Results: Single treatment of genistein at physiologically achievable (low) concentration (<2 µM) induced proliferation of CHO-K1 cells while at a pharmacological (high) concentration (50 and 100 µM) suppressed cells proliferation. Interestingly, treatment of genistein at the physiological concentration in combination with E2 for 24, 48 and 72 h decreased cells viability on CHO-K1 cells compared to untreated cells. Further analysis of the cells showed that 50 µM genistein induced G2/M phase accumulation and induced apoptosis. Moreover, genistein induced cell senescence and increased ROS level. Immunoblotting analysis showed the decreasing of ERalpha, Bcl2, and ppRb protein level upon treatment of 1 µM Gen and 1 nM E2. Conclusion: Our results suggest that the cell proliferation inhibitory mechanism of genistein at pharmacological concentration involved the induction of cell senescence, and the elevation of ROS level. Moreover, the decreased of cells proliferation upon treatment of physiological concentration of genistein in combination with E2 may be correlated with the alteration of ER expression.
Highlights
The proliferation of breast cancers and ovarian cancers usually involves estrogen receptor (ER) pathway in addition to being driven through mitogen-activated protein kinases (MAPKs) signal transduction.[1,2] This pathway will be active when estrogen binds to and activate its receptor, which further activates the expression of genes necessary to spur cell cycle progression
Our results suggest that the cell proliferation inhibitory mechanism of genistein at pharmacological concentration involved the induction of cell senescence, and the elevation of Reactive oxygen species (ROS) level
Further study revealed that genistein exhibits similar physiological effect with estrogens, such as regulating cholesterol metabolism, bone remodelling, and breast gland epithelial cells development.[15]
Summary
The proliferation of breast cancers and ovarian cancers usually involves estrogen receptor (ER) pathway in addition to being driven through mitogen-activated protein kinases (MAPKs) signal transduction.[1,2] This pathway will be active when estrogen binds to and activate its receptor, which further activates the expression of genes necessary to spur cell cycle progression. ERs are needed in several important physiological processes in the body, such as the growth of primary and secondary female sexual tissues, bone integrity, and cholesterol metabolism.[5] ER pathways are very essential, especially to maintain women’s health Disturbance in this pathway may cause the inherent physiological imbalance in body.[6] To address this concern, the development of an anti-cancer agent targeted at the protein kinases that may affect the function of ERs should be given special attention by providing more detailed information of its selectivity following its use later
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