Oxymatrine reverses epithelial-mesenchymal transition in breast cancer cells by depressing α?β3 integrin/FAK/PI3K/Akt signaling activation

Abstract

Yan Chen,1–4,* Lin Chen,1,5,* Jing-Yu Zhang,1 Zong-Yue Chen,1 Ting-ting Liu,1 Yan-Yan Zhang,1–3 Ling-Yun Fu,1–4 Shuang-Qin Fan,1 Min-Qin Zhang,2–4 Shi-quan Gan,1–4 Nen-ling Zhang,1–4 Xiang-Chun Shen1–41The Department of Pharmacology of Materia Medica (The State Key Laboratory of Functions and Applications of Medicinal Plants, The High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability), School of Pharmaceutical Sciences, Guizhou Medical University, Guizhou, People’s Republic of China; 2The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, School of Pharmaceutical Sciences, Guizhou Medical University, Guizhou, People’s Republic of China; 3The Union Key Laboratory of Guiyang City-Guizhou Medical University, School of Pharmaceutical Sciences, Guizhou Medical University, Guizhou, People’s Republic of China; 4The Key Laboratory of Optimal Utilization of Natural Medicine Resources, School of Pharmaceutical Sciences, Guizhou Medical University, Guizhou, People’s Republic of China; 5Department of Pharmacology, Qiannan Medical College For Nationalities, Duyun, Guizhou, People’s Republic of China*These authors contributed equally to this workPurpose: Oxymatrine, an alkaloid extracted from the Chinese herb Sophora flavescens Aiton, possesses anti-inflammatory, anti-immune, anti-hepatic fibrosis, and anti-cancer properties. However, the effects of oxymatrine on epithelial-mesenchymal transition (EMT) of breast cancer cells are still unclear.Aim: The present study was performed to investigate whether oxymatrine reverses EMT in breast cancer cells and to explore the underlying molecular mechanisms.Materials and methods: MTT assay was performed to evaluate cell viability. Wound-healing assay and transwell chamber assay were used to assess cell migration and invasion, respectively. Immunofluorescence and Western blot were used to study the expression of EMT-related molecules and α?β3 integrin/focal adhesion kinase (FAK)/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling transduction. Fibronectin, a physiologic ligand of α?β3 integrin, was used to stimulate α?β3 integrin signaling.Results: Our results demonstrated that oxymatrine effectively suppressed the viability of MDA-MB-231 and 4T1 breast cancer cells, and oxymatrine showed less cytotoxicity on normal breast mammary epithelial MCF-10A cells. In addition, oxymatrine reversed EMT in the MDA-MB-231 and 4T1 cells at nontoxic concentrations. Oxymatrine significantly inhibited cell migration and invasion, downregulated the expression of N-cadherin, vimentin, and Snail in MDA-MB-231 and 4T1 cells, but upregulated the expression of E-cadherin in 4T1 cells. The mechanism revealed that oxymatrine decreased the expression of α? and β3 integrin and their co-localization. It also inhibited α?β3 integrin downstream activation by suppressing the phosphorylation of FAK, PI3K, and Akt. Furthermore, oxymatrine prevented fibronectin-induced EMT and α?β3 integrin/FAK/PI3K/Akt signaling activation.Conclusion: Our results revealed that oxymatrine effectively reversed EMT in breast cancer cells by depressing α?β3 integrin/FAK/PI3K/Akt signaling. Thus, oxymatrine could be a potential therapeutic candidate with anti-metastatic potential for the treatment of breast cancer.Keywords: oxymatrine, breast cancer, α?β3 integrin, epithelial-mesenchymal transition

Keywords

• Oxymatrine
• breast cancer
• ???3 integrin
• epithelial-mesenchymal transition.