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Jian Chen - One of the best experts on this subject based on the ideXlab platform.
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differential ability of Formononetin to stimulate proliferation of endothelial cells and breast cancer cells via a feedback loop involving microrna 375 rasd1 and erα
Molecular Carcinogenesis, 2018Co-Authors: Jian Chen, Xing Zhang, Yong Wang, Yu Ye, Zhaoquan HuangAbstract:For postmenopausal cardiovascular disease, long-term estrogen therapy may increase the risk of breast cancer. To reduce this risk, estrogen may be replaced with the phytoestrogen Formononetin, but how Formononetin acts on vascular endothelial cells (ECs) and breast cancer cells is unclear. Here, we show that low concentrations of Formononetin induced proliferation and inhibited apoptosis more strongly in cultured human umbilical vein endothelial cells (HUVECs) than in breast cancer cells expressing estrogen receptor α (ERα) (MCF-7, BT474) or not (MDA-MB-231), and that this differential stimulation was associated with miR-375 up-regulation in HUVECs. For the first time, we demonstrate the presence of a feedback loop involving miR-375, ras dexamethasone-induced 1 (RASD1), and ERα in normal HUVECs, and we show that Formononetin stimulated this feedback loop in HUVECs but not in MCF-7 or BT474 cells. In all three cell lines, Formononetin increased Akt phosphorylation and Bcl-2 expression. Inhibiting miR-375 blocked these changes and increased proliferation in HUVECs, but not in MCF-7 or BT474 cells. In ovariectomized rats, Formononetin increased uterine weight and caused similar changes in levels of miR-375, RASD1, ERα, and Bcl-2 in aortic ECs as in cultured HUVECs. In mice bearing MCF-7 xenografts, tumor growth was stimulated by 17β-estradiol but not by Formononetin. These results suggest selective action of Formononetin in ECs (proliferation stimulation and apoptosis inhibition) relative to breast cancer cells, possibly via a feedback loop involving miR-375, RASD1, and ERα. This differential effect may explain why Formononetin may not increase the risk of postmenopausal breast cancer.
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Formononetin promotes proliferation that involves a feedback loop of microrna 375 and estrogen receptor alpha in estrogen receptor positive cells
Molecular Carcinogenesis, 2016Co-Authors: Jian Chen, Xing Zhang, Yong Wang, Yu Ye, Zhaoquan HuangAbstract:Formononetin is an O-methylated isoflavone that is isolated from the root of Astragalus membranaceus, and it has antitumorigenic effects. Our previous studies found that Formononetin triggered growth-inhibitory and apoptotic activities in MCF-7 breast cancer cells. To further investigate the potential effect of Formononetin in promoting cell proliferation in estrogen receptor (ER)-positive cells, we used in vivo and in vitro studies to elucidate the possible mechanism. ERα-positive cells (HUVEC, MCF-7) were treated with Formononetin. The CCK8 assay, Hoechst 33258, and flow cytometry were used to assess cell proliferation and apoptosis. mRNA levels of ERα, Bcl-2, and miR-375 were quantified using real-time polymerase chain reaction. ERα, p-Akt, and Bcl-2 expression was determined using Western blot. Compared with the control, low Formononetin concentrations (2–6 μM) stimulated ERα-positive cell proliferation (HUVEC, MCF-7). The more sensitive HUVEC cells were used to study the relevant signaling pathway. After treatment with Formononetin, ERα, miR-375, p-Akt, and Bcl-2 expression was significantly upregulated. The proliferative effect of Formononetin was also blocked by a miR-375 inhibitor or raloxifene pretreatment. Additionally, in the in vivo studies, uterine weight in ovariectomized mice treated with Formononetin increased significantly, but the weight dramatically decreased with raloxifene or miR-375 inhibitor pretreatment before Formononetin. This study demonstrated that Formononetin promoted ERα-positive cell proliferation through miR-375 activation and this mechanism is possibly involving in a miR-375 and ERα feedback loop. © 2015 Wiley Periodicals, Inc.
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estrogen receptor beta mediated proliferative inhibition and apoptosis in human breast cancer by calycosin and Formononetin
Cellular Physiology and Biochemistry, 2013Co-Authors: Jian Chen, Xinge Zhao, Yong Wang, Jing TianAbstract:Background: Calycosin and Formononetin are two main components of isoflavones. In our previous studies, we have respectively reported their antitumor activities on breast cancer cell MCF-7. To further investigate the feasibility of isoflavones in clinically treating breast carcinoma, here we specifically focused on the comparison between calycosin and Formononetin, along with the relevant mechanism. Methods: ER-positive (MCF-7, T-47D) and ER-negative breast cancer cells (MDA-231, MDA-435) were respectively treated with calycosin or Formononetin. Cell proliferation and apoptosis were measured by MTT assay and flow cytometry. mRNA levels of ER beta (ERβ) and miR-375 were quantifed by real-time PCR. Expression of ERβ and insulin-like growth factor 1 receptor (IGF-1R), and activation of poly (ADP-ribose) polymerase 1 (PARP-1) were determined by Western blotting. Results: Both calycosin and Formononetin impaired proliferation and triggered apoptosis of ER-positive breast cancer cells (MCF-7, T-47D) in a time- and dose-dependent manner, especially in the treatment with calycosin. However, no such effect was observed in ER-negative breast cancer cells, indicating the correlation between isoflavones-induced inhibitory effect and ERs. Thus calycosin and most sensitive MCF-7 cells were used to study the relevant signaling pathway. After the treatment of calycosin, ERβ expression was significantly increased in MCF-7 cells, followed by decrease of IGF-1R, activation of PARP-1 cleavage and downregulation of miR-375. Conclusion: Calycosin has an advantage on inhibiting breast cancer growth in comparison with Formononetin, which is obtained by ERβ-mediated regulation of IGF-1R signaling pathways and miR-375 expression.
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Formononetin induced apoptosis by activation of ras p38 mitogen activated protein kinase in estrogen receptor positive human breast cancer cells
Hormone and Metabolic Research, 2012Co-Authors: Jian Chen, L SunAbstract:Formononetin is one of the main active components of red clover plants, and considered as a phytoestrogen. Its pharmacological effects in vivo may be either estrogenic or anti-estrogenic, mainly depending upon the estrogen levels. Our recent studies suggested that Formononetin inactivated IGF1/IGF1R-PI3K/Akt pathways and decreased cyclin D1 mRNA and protein expression in human breast cancer cells in vitro and in vivo. In the present study, we further investigated the molecular mechanisms involved in the induced apoptosis effect of Formononetin on breast cancer cells. Our results suggested that Formononetin inhibited the proliferation of ER-positive MCF-7 cells and T47D cells. In contrast, Formononetin could not inhibit the cell of growth of ER-negative breast cancer cells such as MDA-MB-435 S cells. We further found that Formononetin activated MAPK signaling pathway in a dose-dependent manner, which resulted in the increased ratio of Bax/Bcl-2, and induced apoptosis on MCF-7 cells. However, when MCF-7 cells were pretreated with p38MAPK inhibitor SB203580 before Formononetin, apoptosis induced by Formononetin was significantly attenuated. Thus, we conclude that the induced apoptosis effect of Formononetin on human breast cancer cells were related to Ras-p38MAPK pathway. Considering that red clover plants are widely used clinically, our results provide the foundation for future development of Formononetin for treatment of ER-positive breast cancer.
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Formononetin induced apoptosis of human prostate cancer cells through erk1 2 mitogen activated protein kinase inactivation
Hormone and Metabolic Research, 2012Co-Authors: R Hou, Jian Chen, Jiange Zhang, Y HuangAbstract:Formononetin is a main active component of red clover plants (Trifolium pratense L.), and is considered as a phytoestrogen. Our previous studies demonstrated that Formononetin caused cell cycle arrest at the G0/G1 phase by inactivating insulin-like growth factor 1(IGF1)/IGF1R-phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway in MCF-7 cells. In the present study, we investigated the molecular mechanisms involved in the effect of Formononetin on prostate cancer cells. Our results suggested that higher concentrations of Formononetin inhibited the proliferation of prostate cancer cells (LNCaP and PC-3), while the most striking effect was observed in LNCaP cells. We further found that Formononetin inactivated extracellular signal-regulated kinase1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) signaling pathway in a dose-dependent manner, which resulted in increased the expression levels of BCL2-associated X (Bax) mRNA and protein, and induced apoptosis in LNCaP cells. Thus, we concluded that the induced apoptosis effect of Formononetin on human prostate cancer cells was related to ERK1/2 MAPK-Bax pathway. Considering that red clover plants were widely used clinically, our results provided the foundation for future development of different concentrations Formononetin for treatment of prostate cancer.
Xinge Zhao - One of the best experts on this subject based on the ideXlab platform.
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Formononetin Promotes Cell Cycle Arrest via Downregulation of Akt/Cyclin D1/CDK4 in Human Prostate Cancer Cells
Karger Publishers, 2014Co-Authors: Xinge Zhao, Weihua Huang, Haibiao Yan, Zhian LingAbstract:Background: Formononetin is an O-methylated isoflavone isolated from the root of Astragalus membranaceus. It has already been reported that Formononetin could inhibit cell proliferation and induce cell apoptosis in several cancers, including prostate cancer. This study aimed to further investigate whether cell cycle arrest is involved in Formononetin-mediated antitumor effect in human prostate cancer cells, along with the underlying molecular mechanism. Methods: Human prostate cancer cells PC-3 and DU145 were respectively treated with various concentrations of Formononetin. The inhibitory effect of Formononetin on proliferation of prostate cancer cells was determined using MTT assays and flow cytometry. Next, Formononetin-induced alterations in cyclin D1, CDK4 and Akt expression in PC-3 cells were detected by real-time PCR and western blot. Results: Formononetin dose-dependently inhibited prostate cancer cell proliferation via the induction of cell cycle arrest at G0/G1 phase in vitro, which was more evident in PC-3 cells. Meanwhile, concomitant with reduced phosphorylation of Akt in PC-3 cells, Formononetin remarkably downregulated expression levels of cyclin D1 and CDK4 in a dose-dependent manner. More interestingly, in the in vivo studies, Formononetin showed a noticeable inhibition of tumor growth in recipient mice. Conclusion: Formononetin could exhibit inhibitory activity against human prostate cancer cells in vivo and in vitro, which is associated with G1 cell cycle arrest by inactivation of Akt/cyclin D1/CDK4. Therefore, Formononetin may be used as a candidate agent for clinical treatment of prostate cancer in the future
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Formononetin promotes cell cycle arrest via downregulation of akt cyclin d1 cdk4 in human prostate cancer cells
Cellular Physiology and Biochemistry, 2014Co-Authors: Xinge Zhao, Weihua Huang, Haibiao Yan, Zhian LingAbstract:Background: Formononetin is an O-methylated isoflavone isolated from the root of Astragalus membranaceus. It has already been reported that Formononetin could inhibit cell proliferation and induce cell apoptosis in several cancers, including prostate cancer. This study aimed to further investigate whether cell cycle arrest is involved in Formononetin-mediated antitumor effect in human prostate cancer cells, along with the underlying molecular mechanism. Methods: Human prostate cancer cells PC-3 and DU145 were respectively treated with various concentrations of Formononetin. The inhibitory effect of Formononetin on proliferation of prostate cancer cells was determined using MTT assays and flow cytometry. Next, Formononetin-induced alterations in cyclin D1, CDK4 and Akt expression in PC-3 cells were detected by real-time PCR and western blot. Results: Formononetin dose-dependently inhibited prostate cancer cell proliferation via the induction of cell cycle arrest at G0/G1 phase in vitro, which was more evident in PC-3 cells. Meanwhile, concomitant with reduced phosphorylation of Akt in PC-3 cells, Formononetin remarkably downregulated expression levels of cyclin D1 and CDK4 in a dose-dependent manner. More interestingly, in the in vivo studies, Formononetin showed a noticeable inhibition of tumor growth in recipient mice. Conclusion: Formononetin could exhibit inhibitory activity against human prostate cancer cells in vivo and in vitro, which is associated with G1 cell cycle arrest by inactivation of Akt/cyclin D1/CDK4. Therefore, Formononetin may be used as a candidate agent for clinical treatment of prostate cancer in the future.
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estrogen receptor beta mediated proliferative inhibition and apoptosis in human breast cancer by calycosin and Formononetin
Cellular Physiology and Biochemistry, 2013Co-Authors: Jian Chen, Xinge Zhao, Yong Wang, Jing TianAbstract:Background: Calycosin and Formononetin are two main components of isoflavones. In our previous studies, we have respectively reported their antitumor activities on breast cancer cell MCF-7. To further investigate the feasibility of isoflavones in clinically treating breast carcinoma, here we specifically focused on the comparison between calycosin and Formononetin, along with the relevant mechanism. Methods: ER-positive (MCF-7, T-47D) and ER-negative breast cancer cells (MDA-231, MDA-435) were respectively treated with calycosin or Formononetin. Cell proliferation and apoptosis were measured by MTT assay and flow cytometry. mRNA levels of ER beta (ERβ) and miR-375 were quantifed by real-time PCR. Expression of ERβ and insulin-like growth factor 1 receptor (IGF-1R), and activation of poly (ADP-ribose) polymerase 1 (PARP-1) were determined by Western blotting. Results: Both calycosin and Formononetin impaired proliferation and triggered apoptosis of ER-positive breast cancer cells (MCF-7, T-47D) in a time- and dose-dependent manner, especially in the treatment with calycosin. However, no such effect was observed in ER-negative breast cancer cells, indicating the correlation between isoflavones-induced inhibitory effect and ERs. Thus calycosin and most sensitive MCF-7 cells were used to study the relevant signaling pathway. After the treatment of calycosin, ERβ expression was significantly increased in MCF-7 cells, followed by decrease of IGF-1R, activation of PARP-1 cleavage and downregulation of miR-375. Conclusion: Calycosin has an advantage on inhibiting breast cancer growth in comparison with Formononetin, which is obtained by ERβ-mediated regulation of IGF-1R signaling pathways and miR-375 expression.
Zhian Ling - One of the best experts on this subject based on the ideXlab platform.
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Formononetin Promotes Cell Cycle Arrest via Downregulation of Akt/Cyclin D1/CDK4 in Human Prostate Cancer Cells
Karger Publishers, 2014Co-Authors: Xinge Zhao, Weihua Huang, Haibiao Yan, Zhian LingAbstract:Background: Formononetin is an O-methylated isoflavone isolated from the root of Astragalus membranaceus. It has already been reported that Formononetin could inhibit cell proliferation and induce cell apoptosis in several cancers, including prostate cancer. This study aimed to further investigate whether cell cycle arrest is involved in Formononetin-mediated antitumor effect in human prostate cancer cells, along with the underlying molecular mechanism. Methods: Human prostate cancer cells PC-3 and DU145 were respectively treated with various concentrations of Formononetin. The inhibitory effect of Formononetin on proliferation of prostate cancer cells was determined using MTT assays and flow cytometry. Next, Formononetin-induced alterations in cyclin D1, CDK4 and Akt expression in PC-3 cells were detected by real-time PCR and western blot. Results: Formononetin dose-dependently inhibited prostate cancer cell proliferation via the induction of cell cycle arrest at G0/G1 phase in vitro, which was more evident in PC-3 cells. Meanwhile, concomitant with reduced phosphorylation of Akt in PC-3 cells, Formononetin remarkably downregulated expression levels of cyclin D1 and CDK4 in a dose-dependent manner. More interestingly, in the in vivo studies, Formononetin showed a noticeable inhibition of tumor growth in recipient mice. Conclusion: Formononetin could exhibit inhibitory activity against human prostate cancer cells in vivo and in vitro, which is associated with G1 cell cycle arrest by inactivation of Akt/cyclin D1/CDK4. Therefore, Formononetin may be used as a candidate agent for clinical treatment of prostate cancer in the future
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Formononetin promotes cell cycle arrest via downregulation of akt cyclin d1 cdk4 in human prostate cancer cells
Cellular Physiology and Biochemistry, 2014Co-Authors: Xinge Zhao, Weihua Huang, Haibiao Yan, Zhian LingAbstract:Background: Formononetin is an O-methylated isoflavone isolated from the root of Astragalus membranaceus. It has already been reported that Formononetin could inhibit cell proliferation and induce cell apoptosis in several cancers, including prostate cancer. This study aimed to further investigate whether cell cycle arrest is involved in Formononetin-mediated antitumor effect in human prostate cancer cells, along with the underlying molecular mechanism. Methods: Human prostate cancer cells PC-3 and DU145 were respectively treated with various concentrations of Formononetin. The inhibitory effect of Formononetin on proliferation of prostate cancer cells was determined using MTT assays and flow cytometry. Next, Formononetin-induced alterations in cyclin D1, CDK4 and Akt expression in PC-3 cells were detected by real-time PCR and western blot. Results: Formononetin dose-dependently inhibited prostate cancer cell proliferation via the induction of cell cycle arrest at G0/G1 phase in vitro, which was more evident in PC-3 cells. Meanwhile, concomitant with reduced phosphorylation of Akt in PC-3 cells, Formononetin remarkably downregulated expression levels of cyclin D1 and CDK4 in a dose-dependent manner. More interestingly, in the in vivo studies, Formononetin showed a noticeable inhibition of tumor growth in recipient mice. Conclusion: Formononetin could exhibit inhibitory activity against human prostate cancer cells in vivo and in vitro, which is associated with G1 cell cycle arrest by inactivation of Akt/cyclin D1/CDK4. Therefore, Formononetin may be used as a candidate agent for clinical treatment of prostate cancer in the future.
Weihua Huang - One of the best experts on this subject based on the ideXlab platform.
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Formononetin Promotes Cell Cycle Arrest via Downregulation of Akt/Cyclin D1/CDK4 in Human Prostate Cancer Cells
Karger Publishers, 2014Co-Authors: Xinge Zhao, Weihua Huang, Haibiao Yan, Zhian LingAbstract:Background: Formononetin is an O-methylated isoflavone isolated from the root of Astragalus membranaceus. It has already been reported that Formononetin could inhibit cell proliferation and induce cell apoptosis in several cancers, including prostate cancer. This study aimed to further investigate whether cell cycle arrest is involved in Formononetin-mediated antitumor effect in human prostate cancer cells, along with the underlying molecular mechanism. Methods: Human prostate cancer cells PC-3 and DU145 were respectively treated with various concentrations of Formononetin. The inhibitory effect of Formononetin on proliferation of prostate cancer cells was determined using MTT assays and flow cytometry. Next, Formononetin-induced alterations in cyclin D1, CDK4 and Akt expression in PC-3 cells were detected by real-time PCR and western blot. Results: Formononetin dose-dependently inhibited prostate cancer cell proliferation via the induction of cell cycle arrest at G0/G1 phase in vitro, which was more evident in PC-3 cells. Meanwhile, concomitant with reduced phosphorylation of Akt in PC-3 cells, Formononetin remarkably downregulated expression levels of cyclin D1 and CDK4 in a dose-dependent manner. More interestingly, in the in vivo studies, Formononetin showed a noticeable inhibition of tumor growth in recipient mice. Conclusion: Formononetin could exhibit inhibitory activity against human prostate cancer cells in vivo and in vitro, which is associated with G1 cell cycle arrest by inactivation of Akt/cyclin D1/CDK4. Therefore, Formononetin may be used as a candidate agent for clinical treatment of prostate cancer in the future
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Formononetin promotes cell cycle arrest via downregulation of akt cyclin d1 cdk4 in human prostate cancer cells
Cellular Physiology and Biochemistry, 2014Co-Authors: Xinge Zhao, Weihua Huang, Haibiao Yan, Zhian LingAbstract:Background: Formononetin is an O-methylated isoflavone isolated from the root of Astragalus membranaceus. It has already been reported that Formononetin could inhibit cell proliferation and induce cell apoptosis in several cancers, including prostate cancer. This study aimed to further investigate whether cell cycle arrest is involved in Formononetin-mediated antitumor effect in human prostate cancer cells, along with the underlying molecular mechanism. Methods: Human prostate cancer cells PC-3 and DU145 were respectively treated with various concentrations of Formononetin. The inhibitory effect of Formononetin on proliferation of prostate cancer cells was determined using MTT assays and flow cytometry. Next, Formononetin-induced alterations in cyclin D1, CDK4 and Akt expression in PC-3 cells were detected by real-time PCR and western blot. Results: Formononetin dose-dependently inhibited prostate cancer cell proliferation via the induction of cell cycle arrest at G0/G1 phase in vitro, which was more evident in PC-3 cells. Meanwhile, concomitant with reduced phosphorylation of Akt in PC-3 cells, Formononetin remarkably downregulated expression levels of cyclin D1 and CDK4 in a dose-dependent manner. More interestingly, in the in vivo studies, Formononetin showed a noticeable inhibition of tumor growth in recipient mice. Conclusion: Formononetin could exhibit inhibitory activity against human prostate cancer cells in vivo and in vitro, which is associated with G1 cell cycle arrest by inactivation of Akt/cyclin D1/CDK4. Therefore, Formononetin may be used as a candidate agent for clinical treatment of prostate cancer in the future.
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Formononetin induces cell cycle arrest of human breast cancer cells via igf1 pi3k akt pathways in vitro and in vivo
Hormone and Metabolic Research, 2011Co-Authors: Jian Chen, Weihua Huang, J Zeng, M Xin, Xi ChenAbstract:Formononetin is one of the main components of red clover plants, and is considered as a typical phytoestrogen. This study further investigated that Formononetin inactivated IGF1/IGF1R-PI3K/Akt pathways and decreased cyclin D1 mRNA and protein expression in human breast cancer cells in vitro and in vivo. MCF-7 cells were treated with different concentrations of Formononetin. The proliferation of the cells treated with Formononetin was tested by MTT assay. The cell cycle in the treated cells was examined by flow cytometry. The levels of p-IGF-1 R, p-Akt, and cyclin D1 protein expression and cyclin D1 mRNA expression in the treated cells were determined by Western blot and RT-PCR, respectively. In addition, the antitumor activity of Formononetin was evaluated in nude mice bearing orthotopic tumor implants. Compared with the control, Formononetin inhibited the proliferation of MCF-7 cells and effectively induced cell cycle arrest. The levels of p-IGF-1 R, p-Akt, cyclin D1 protein expression, and cyclin D1 mRNA expression were also downregulated. On the other hand, Formononetin also prevented the tumor growth of human breast cancer cells in nude mouse xenografts. These results show that Formononetin causes cell cycle arrest at the G0/G1 phase by inactivating IGF1/IGF1R-PI3K/Akt pathways and decreasing cyclin D1 mRNA and protein expression, indicating the use of Formononetin in the prevention of breast cancer carcinogenesis.
Yong Wang - One of the best experts on this subject based on the ideXlab platform.
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differential ability of Formononetin to stimulate proliferation of endothelial cells and breast cancer cells via a feedback loop involving microrna 375 rasd1 and erα
Molecular Carcinogenesis, 2018Co-Authors: Jian Chen, Xing Zhang, Yong Wang, Yu Ye, Zhaoquan HuangAbstract:For postmenopausal cardiovascular disease, long-term estrogen therapy may increase the risk of breast cancer. To reduce this risk, estrogen may be replaced with the phytoestrogen Formononetin, but how Formononetin acts on vascular endothelial cells (ECs) and breast cancer cells is unclear. Here, we show that low concentrations of Formononetin induced proliferation and inhibited apoptosis more strongly in cultured human umbilical vein endothelial cells (HUVECs) than in breast cancer cells expressing estrogen receptor α (ERα) (MCF-7, BT474) or not (MDA-MB-231), and that this differential stimulation was associated with miR-375 up-regulation in HUVECs. For the first time, we demonstrate the presence of a feedback loop involving miR-375, ras dexamethasone-induced 1 (RASD1), and ERα in normal HUVECs, and we show that Formononetin stimulated this feedback loop in HUVECs but not in MCF-7 or BT474 cells. In all three cell lines, Formononetin increased Akt phosphorylation and Bcl-2 expression. Inhibiting miR-375 blocked these changes and increased proliferation in HUVECs, but not in MCF-7 or BT474 cells. In ovariectomized rats, Formononetin increased uterine weight and caused similar changes in levels of miR-375, RASD1, ERα, and Bcl-2 in aortic ECs as in cultured HUVECs. In mice bearing MCF-7 xenografts, tumor growth was stimulated by 17β-estradiol but not by Formononetin. These results suggest selective action of Formononetin in ECs (proliferation stimulation and apoptosis inhibition) relative to breast cancer cells, possibly via a feedback loop involving miR-375, RASD1, and ERα. This differential effect may explain why Formononetin may not increase the risk of postmenopausal breast cancer.
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Formononetin promotes proliferation that involves a feedback loop of microrna 375 and estrogen receptor alpha in estrogen receptor positive cells
Molecular Carcinogenesis, 2016Co-Authors: Jian Chen, Xing Zhang, Yong Wang, Yu Ye, Zhaoquan HuangAbstract:Formononetin is an O-methylated isoflavone that is isolated from the root of Astragalus membranaceus, and it has antitumorigenic effects. Our previous studies found that Formononetin triggered growth-inhibitory and apoptotic activities in MCF-7 breast cancer cells. To further investigate the potential effect of Formononetin in promoting cell proliferation in estrogen receptor (ER)-positive cells, we used in vivo and in vitro studies to elucidate the possible mechanism. ERα-positive cells (HUVEC, MCF-7) were treated with Formononetin. The CCK8 assay, Hoechst 33258, and flow cytometry were used to assess cell proliferation and apoptosis. mRNA levels of ERα, Bcl-2, and miR-375 were quantified using real-time polymerase chain reaction. ERα, p-Akt, and Bcl-2 expression was determined using Western blot. Compared with the control, low Formononetin concentrations (2–6 μM) stimulated ERα-positive cell proliferation (HUVEC, MCF-7). The more sensitive HUVEC cells were used to study the relevant signaling pathway. After treatment with Formononetin, ERα, miR-375, p-Akt, and Bcl-2 expression was significantly upregulated. The proliferative effect of Formononetin was also blocked by a miR-375 inhibitor or raloxifene pretreatment. Additionally, in the in vivo studies, uterine weight in ovariectomized mice treated with Formononetin increased significantly, but the weight dramatically decreased with raloxifene or miR-375 inhibitor pretreatment before Formononetin. This study demonstrated that Formononetin promoted ERα-positive cell proliferation through miR-375 activation and this mechanism is possibly involving in a miR-375 and ERα feedback loop. © 2015 Wiley Periodicals, Inc.
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low concentration of Formononetin stimulates the proliferation of nasopharyngeal carcinoma cell line cne2 by upregulating bcl 2 and p erk1 2 expression
Pharmaceutical Biology, 2016Co-Authors: Yan Hong Guo, Yong Wang, Min XinAbstract:AbstractContext Formononetin is a typical phytoestrogen, which is a bioactive component found in red clover plants. Previous studies have shown that Formononetin inhibits the proliferation of several types of cancer cells, including prostate cancer and osteosarcoma. However, how Formononetin affects the proliferation of CNE2 is not clear.Objective The objective of this study is to investigate the effects of Formononetin on nasopharyngeal carcinoma cells in vitro, along with the underlying mechanism.Materials and methods CNE2 cells were incubated with various concentrations of Formononetin (0, 0.1, 0.2, 0.3 and 1 μM) for 48 h. Cell proliferation was measured by [3-(4,5-dimethylthiazol-2-yl)]-2,5-diphenyltetrazolium bromide (MTT) assay, while the rate of apoptosis was measured by flow cytometry. Bcl-2 and bax mRNA expression levels were determined by real time polymerase chain reaction (RT-PCR), while p-ERK1/2 and bcl-2 protein expression levels were quantified by Western blotting.Results Formononetin promo...
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Formononetin mediates neuroprotection against cerebral ischemia reperfusion in rats via downregulation of the bax bcl 2 ratio and upregulation pi3k akt signaling pathway
Journal of the Neurological Sciences, 2014Co-Authors: Kun Liang, Yong Wang, Jianfeng ZhangAbstract:Abstract Isoflavone Formononetin is a typical phytoestrogen isolated from Chinese medical herb red clover. It has been reported that estrogens have neuroprotective properties, and dietary intake of phytoestrogens could reduce stroke injury in cerebral ischemia/reperfusion (I/R) animal models. In the present research, we sought to investigate the molecular mechanisms underlying the neuroprotective effects of Formononetin on I/R rats. Male Sprague–Dawley rats were subjected to a 2 h period of right middle cerebral artery occlusion (MCAO) followed by 24 h of reperfusion. Then neurological deficits and brain edema were evaluated. To provide insight into the functions of phosphatidylinositol 3-kinase (PI3K)/Akt and MAPK (mitogen-activated protein kinase) signaling pathway in Formononetin-induced neuroprotection, the expression of ER-α, Bax, Bcl-2, p-Akt (phosphorylated protein kinase B), and p-ERK1/2 (phosphorylated extracellular signal-regulated kinases 1/2) was determined by qPCR or Western blot assay. Consequently, we found that Formononetin has significantly reduced the infarcted volume and the brain water content, and improved the neurological deficit. Formononetin also exhibited an upregulation in ER-α and p-Akt, a downregulation in the ratio of Bax/Bcl-2. However, Formononetin had little effect on p-ERK1/2 proteins expression. Taken together, Formononetin has shown neuroprotective effects in cerebral I/R rats, and the molecular mechanisms may correlate with the downregulation of the Bax/Bcl-2 ratio and the activation of PI3K/Akt signaling pathway.
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estrogen receptor beta mediated proliferative inhibition and apoptosis in human breast cancer by calycosin and Formononetin
Cellular Physiology and Biochemistry, 2013Co-Authors: Jian Chen, Xinge Zhao, Yong Wang, Jing TianAbstract:Background: Calycosin and Formononetin are two main components of isoflavones. In our previous studies, we have respectively reported their antitumor activities on breast cancer cell MCF-7. To further investigate the feasibility of isoflavones in clinically treating breast carcinoma, here we specifically focused on the comparison between calycosin and Formononetin, along with the relevant mechanism. Methods: ER-positive (MCF-7, T-47D) and ER-negative breast cancer cells (MDA-231, MDA-435) were respectively treated with calycosin or Formononetin. Cell proliferation and apoptosis were measured by MTT assay and flow cytometry. mRNA levels of ER beta (ERβ) and miR-375 were quantifed by real-time PCR. Expression of ERβ and insulin-like growth factor 1 receptor (IGF-1R), and activation of poly (ADP-ribose) polymerase 1 (PARP-1) were determined by Western blotting. Results: Both calycosin and Formononetin impaired proliferation and triggered apoptosis of ER-positive breast cancer cells (MCF-7, T-47D) in a time- and dose-dependent manner, especially in the treatment with calycosin. However, no such effect was observed in ER-negative breast cancer cells, indicating the correlation between isoflavones-induced inhibitory effect and ERs. Thus calycosin and most sensitive MCF-7 cells were used to study the relevant signaling pathway. After the treatment of calycosin, ERβ expression was significantly increased in MCF-7 cells, followed by decrease of IGF-1R, activation of PARP-1 cleavage and downregulation of miR-375. Conclusion: Calycosin has an advantage on inhibiting breast cancer growth in comparison with Formononetin, which is obtained by ERβ-mediated regulation of IGF-1R signaling pathways and miR-375 expression.