Formononetin promotes angiogenesis through the estrogen receptor alpha-enhanced ROCK pathway

Li, Shang; Dang, Yanan; Zhou, Xuelin; Huang, Bin; Huang, Xiao-Hui; Zhang, Zherui; Kwan, Yiu Wa; Chan, Shun‐Wan; Leung, George Pak-Heng; Lee, Simon Ming‐Yuen; Hoi, Maggie Pui Man

doi:10.1038/srep16815

Cited by 42 publications

(32 citation statements)

References 35 publications

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“…It is known that in breast cancer metastasis and tumor formation, the migration of cells is implicated [38]. To determine whether red clover preparations are involved in that process, we adopted the scratch wound assay.…”

Section: The Effect Of Trifolium Pratense L On Migration and Attachmmentioning

confidence: 99%

“…Among those isoflavones identified in the extracts, formononetin was present in the largest amount; however, its concentration was almost four times higher in extracts obtained after sprouts fermentation-CUF and CUFH. Studies performed by Li et al identified formononetin as an inducer of endothelial cell migration via recruiting of ERα/ROCK-II (Rho-associated protein kinase) activated complex formation [38]. In signal transduction, ROCK kinase plays a crucial role in cytoskeleton regulation by phosphorylating the myosin-binding subunit of myosin light chain phosphatase, leading to F-actin stress fibers' formation and focal adhesions, allowing cell migration [38].…”

Section: The Effect Of Trifolium Pratense L On Migration and Attachmmentioning

confidence: 99%

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The Effects of Trifolium pratense L. Sprouts’ Phenolic Compounds on Cell Growth and Migration of MDA-MB-231, MCF-7 and HUVEC Cells

Zakłos‐Szyda

Budryn

2020

Nutrients

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Uncontrolled growth and migration and invasion abilities are common for cancer cells in malignant tumors with low therapeutic effectiveness and high mortality and morbidity. Estrogen receptor β (ERβ), as a member of the nuclear receptor superfamily, shows potent tumor suppressive activities in many cancers. Phytoestrogens’ structural resemblance to 17 β-estradiol allows their binding to ERβ isoform predominantly, and therefore, expression of genes connected with elevated proliferation, motility and invasiveness of cancer cells may be downregulated. Among polyphenolic compounds with phytoestrogenic activity, there are isoflavones from Trifolium pratense L. (red clover) sprouts, containing high amounts of formononetin and biochanin A and their glycosides. To determine the source of the most biologically active isoflavones, we obtained four extracts from sprouts before and after their lactic fermentation and/or β-glucosidase treatment. Our previous results of ITC (isothermal titration calorimetry) modelling and a docking simulation showed clover isoflavones’ affinity to ERβ binding, which may downregulate cancer cell proliferation and migration. Thus, the biological activity of T. pratense sprouts’ extracts was checked under in vitro conditions against highly invasive human breast cancer cell line MDA-MB-231 and non-invasive human breast cancer cell line MCF-7 cells. To compare extracts’ activities acquired for cancer cells with those activities against normal cells, as a third model we choose human umbilical vein endothelial cells (HUVEC), which, due to their migration abilities, are involved in blood vessel formation. Extracts obtained from fermented sprouts at IC0 dosages were able to inhibit migration of breast cancer cells through their influence on intracellular ROS generation; membrane stiffening; adhesion; regulation of MMP-9, N-cadherin and E-cadherin at transcriptional level; or VEGF secretion. Simultaneously, isolated phenolics revealed no toxicity against normal HUVEC cells. In the manuscript, we proposed a preliminary mechanism accounting for the in vitro activity of Trifolium pratense L. isoflavones. In this manner, T. pratense sprouts, especially after their lactic fermentation, can be considered a potent source of biological active phytoestrogens and a dietary supplement with anti-cancer and anti-invasion properties.

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Section: The Effect Of Trifolium Pratense L On Migration and Attachmmentioning

confidence: 99%

Section: The Effect Of Trifolium Pratense L On Migration and Attachmmentioning

confidence: 99%

The Effects of Trifolium pratense L. Sprouts’ Phenolic Compounds on Cell Growth and Migration of MDA-MB-231, MCF-7 and HUVEC Cells

Zakłos‐Szyda

Budryn

2020

Nutrients

View full text Add to dashboard Cite

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“…How formononetin affects ECs and breast cancer cells is unclear. One study reported that formononetin promoted angiogenesis through the ROCK pathway, while another reported that it inhibited angiogenesis and breast cancer growth . Such conflicting results may reflect concentration‐dependent effects.…”

Section: Introductionmentioning

confidence: 99%

“…One study reported that formononetin promoted angiogenesis through the ROCK pathway, 12 while another reported that it inhibited angiogenesis and breast cancer growth. 13 Such conflicting results may reflect concentration-dependent effects. Indeed, studies from our laboratory demonstrated that formononetin can stimulate breast cancer cell growth at concentrations up to 10 μM but inhibit growth at concentrations above 30 μM.…”

mentioning

confidence: 99%

Differential ability of formononetin to stimulate proliferation of endothelial cells and breast cancer cells via a feedback loop involving MicroRNA‐375, RASD1, and ERα

Chen

Zhang

Wang

et al. 2018

Molecular Carcinogenesis

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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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“…Rho kinase (ROCK) is one of the first downstream targets of RhoA. RhoA/ROCK signaling regulates cell functions, including contraction [10], migration [11], adhesion [12], and cell cycle progression [13]. RhoA/ROCK signaling has recently attracted extensive attention as an important contributor to diabetic renal disease [14].…”

mentioning

confidence: 99%

Rutin Prevents High Glucose-Induced Renal Glomerular Endothelial Hyperpermeability by Inhibiting the ROS/Rhoa/ROCK Signaling Pathway

et al. 2016

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Diabetic nephropathy is a progressive kidney disease caused by damage to the capillaries in the glomeruli. Endothelial dysfunction is an early sign of diabetic cardiovascular disease and may contribute to progressive diabetic nephropathy. Hyperglycemia-induced endothelial hyperpermeability is crucial to diabetic nephropathy. Rutin has beneficial effects on diabetic nephropathy, but the exact mechanisms of its protective effect remain elusive. The aim of this study was to assess the role of pretreatment with rutin in an in vitro model of hyperglycemia-induced barrier dysfunction in human renal glomerular endothelial cells. Human renal glomerular endothelial cells were exposed to rutin and/or hyperglycemia for 24?h. Hyperglycemia increased permeability and decreased the junction protein occludin in the cell-cell junction area and the total expression in human renal glomerular endothelial cells, whereas rutin treatment significantly corrected these abnormalities. Furthermore, hyperglycemia-induced activation of RhoA/ROCK was reversed by treatment with rutin or the knockdown of ROCK2. Interestingly, rutin prevented hyperglycemia-induced hyperpermeability, and dysfunction of the tight junction, a high level of reactive oxygen species, and activation of RhoA/ROCK were significantly abolished with the knockdown of Nrf2. In conclusion, rutin significantly prevented hyperglycemia-disrupted renal endothelial barrier function by inhibiting the RhoA/ROCK signaling pathway through decreasing reactive oxygen species, which was mediated by the activation of Nrf2. Our results may explain, at least in part, some beneficial effects of rutin that may be applicable to the treatment of vascular disorders in diabetic nephropathy.

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Formononetin promotes angiogenesis through the estrogen receptor alpha-enhanced ROCK pathway

Cited by 42 publications

References 35 publications

The Effects of Trifolium pratense L. Sprouts’ Phenolic Compounds on Cell Growth and Migration of MDA-MB-231, MCF-7 and HUVEC Cells

The Effects of Trifolium pratense L. Sprouts’ Phenolic Compounds on Cell Growth and Migration of MDA-MB-231, MCF-7 and HUVEC Cells

Differential ability of formononetin to stimulate proliferation of endothelial cells and breast cancer cells via a feedback loop involving MicroRNA‐375, RASD1, and ERα

Rutin Prevents High Glucose-Induced Renal Glomerular Endothelial Hyperpermeability by Inhibiting the ROS/Rhoa/ROCK Signaling Pathway

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