Formononetin Inhibits Migration and Invasion of MDA-MB-231 and 4T1 Breast Cancer Cells by Suppressing MMP-2 and MMP-9 Through PI3K/AKT Signaling Pathways

Zhou, Renhong; Xu, Limin; Ye, M; Liao, Min; Chen, H

doi:10.1055/s-0034-1376977

Cited by 147 publications

(134 citation statements)

References 12 publications

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“…In addition, MMP‐2 and MMP‐9 serve as important downstream effectors of AKT 10, 23, 24 and are involved in cell motility and VM formation 10, 26. Therefore, the hypothesis that Rictor regulates VM via the AKT‐MMP‐2/9 pathway is reasonable.…”

Section: Discussionmentioning

confidence: 99%

Rictor regulates the vasculogenic mimicry of melanoma via the AKT‐MMP‐2/9 pathway

Liang

Sun

Zhao

et al. 2017

J Cellular Molecular Medi

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Vasculogenic mimicry (VM)‐positive melanomas are usually associated with poor prognosis. Rictor, the key component of the rapamycin‐insensitive complex of mTOR (mTORC2), is up‐regulated in several cancers, especially in melanomas with poor prognosis. The aim of this study was to investigate the role of Rictor in the regulation of VM and the mechanism underlying this possible regulation. VM channels were found in 35 of 81 tested melanoma samples and high Rictor expression correlated with VM structures. Moreover, Kaplan–Meier survival curves indicated that VM structures and high Rictor expression correlated with shorter survival in patients with melanoma. In vitro, Rictor knockdown by short hairpin RNA (shRNA) significantly inhibited the ability of A375 and MUM‐2B melanoma cells to form VM structures, as evidenced by most tubes remaining open. Cell cycle analysis revealed that Rictor knockdown blocked cell growth and resulted in the accumulation of cells in G2/M phase, and cell migration and invasion were greatly affected after Rictor down‐regulation. Western blotting assays indicated that down‐regulating Rictor significantly inhibited the phosphorylation of AKT at Ser473 and Thr308, which subsequently inhibited the expression and activity of downstream MMP‐2/9, as confirmed by real‐time PCR and gelatin Zymography. MK‐2206, a small‐molecule inhibitor of AKT, similarly inhibited the activity of AKT and secretion of MMP‐2/9, further supporting that Rictor down‐regulation inhibits the phosphorylation of AKT and activity of downstream MMP‐2/9 to affect VM formation. In conclusion, Rictor plays an important role in melanoma VM via the Rictor—AKT—MMP‐2/9 signalling pathway.

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Section: Discussionmentioning

confidence: 99%

Rictor regulates the vasculogenic mimicry of melanoma via the AKT‐MMP‐2/9 pathway

Liang

Sun

Zhao

et al. 2017

J Cellular Molecular Medi

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“…MMP-9 has been considered as a potential downstream signal molecule of the Akt pathway. Some potential anticancer agents such as formononetin and piceatannol were shown to inhibit breast cancer cell invasion by suppressing MMP-9 through blocking the Akt pathway 47,48. Moreover, the activation of Akt axis is also emerging as a central feature of EMT 49.…”

Section: Discussionmentioning

confidence: 99%

Cyclooxygenase-2 in tumor-associated macrophages promotes metastatic potential of breast cancer cells through Akt pathway

Gan¹,

Qiu²,

Huang³

et al. 2016

Int. J. Biol. Sci.

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Tumor-associated macrophages (TAMs) promote cancer development and progression by releasing various cytokines and chemokines. Previously, we have found that the number of COX-2+ TAMs was associated with lymph node metastasis in breast cancer. However, the mechanism remains enigmatic. In this study, we show that COX-2 in breast TAMs enhances the metastatic potential of breast cancer cells. COX-2 in TAMs induces MMP-9 expression and promotes epithelial-mesenchymal transition (EMT) in breast cancer cells. In addition, COX-2/PGE2 induces IL-6 release in macrophages. Furthermore, we find that the activation of Akt pathway in cancer cells is crucial for the pro-metastatic effect of COX-2+ TAMs by regulating MMP-9 and EMT. These findings indicate that TAMs facilitate breast cancer cell metastasis through COX-2-mediated intercellular communication.

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“…In addition, it has been demonstrated that AKT signaling is involved in regulating the expression of a number of cell cycle-related proteins and MMPs (9,31,32). Therefore, the activity of AKT signaling after treatment with PDGF-BB with or without formononetin was evaluated in the present study.…”

Section: Discussionmentioning

confidence: 98%

“…It has been well established that MMP2 and MMP9 play key roles in the regulation of cell migration (9). Therefore, the protein expression levels of MMP2 and MMP9 were determined in the VSMCs in each group.…”

Section: Formononetin Suppressed Pdgf-bb-induced Upregulation Of Mmp2mentioning

confidence: 99%

“…As an important component of A. membranaceus, formononetin has also been demonstrated to have various pharmacological effects. For instance, previous studies have indicated that formononetin is able to inhibit tumor cell proliferation, migration and invasion (8,9), induce tumor cell apoptosis (10), attenuate hydrogen peroxide-induced retinal ganglion cell apoptosis (11), as well as mediate neuroprotection against cerebral ischemia/reperfusion (12).…”

Section: Introductionmentioning

confidence: 99%

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Suppressive effect of formononetin on platelet-derived growth factor-BB-stimulated proliferation and migration of vascular smooth muscle cells

Chen

Liu

Cai

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) has been implicated in intimal hyperplasia, atherosclerosis and restenosis following percutaneous coronary intervention. Formononetin, a phytoestrogen extracted from the root of Astragalus membranaceus, has been widely used in Chinese tradition medicine due to its protective effects against certain symptoms of cancer, hypertension, inflammation, hypoxia-induced cytotoxicity and ovariectomy-induced bone loss. However, the effect of formononetin on platelet-derived growth factor (PDGF)-BB-induced proliferation and migration of VSMCs, as well as the underlying molecular mechanism, remains largely unclear. In the present study, treatment with formononetin significantly inhibited PDGF-BB-induced proliferation and migration of human VSMCs. Investigation into the underlying molecular mechanism revealed that the administration of formononetin suppressed PDGF-BB-stimulated switch of VSMCs to a proliferative phenotype. Furthermore, treatment with formononetin inhibited the PDGF-BB-induced upregulation of cell cycle-related proteins, matrix metalloproteinase (MMP2) and MMP9. In addition, the that administration of formononetin inhibited the phosphorylation of AKT induced by PDGF-BB in VSMCs. The present results suggest that formononetin has a suppressive effect on PDGF-BB-stimulated VSMCs proliferation and migration, which may occur partly via the inhibition of AKT signaling pathway. Therefore, formononetin may be useful for the treatment of intimal hyperplasia, atherosclerosis and restenosis.

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Formononetin Inhibits Migration and Invasion of MDA-MB-231 and 4T1 Breast Cancer Cells by Suppressing MMP-2 and MMP-9 Through PI3K/AKT Signaling Pathways

Cited by 147 publications

References 12 publications

Rictor regulates the vasculogenic mimicry of melanoma via the AKT‐MMP‐2/9 pathway

Rictor regulates the vasculogenic mimicry of melanoma via the AKT‐MMP‐2/9 pathway

Cyclooxygenase-2 in tumor-associated macrophages promotes metastatic potential of breast cancer cells through Akt pathway

Suppressive effect of formononetin on platelet-derived growth factor-BB-stimulated proliferation and migration of vascular smooth muscle cells

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