Abstract
Mitogen-activated protein kinases/Extracellular signal-regulated kinase (MAPK/ERK) pathway is essential for migration and invasion of malignant glioma. It is efficient to inhibit migration and invasion of glioma cells by targeting this pathway. Oleanolic acid (OA) has been well demonstrated to suppress survival, growth and angiogenesis of glioma cells. However, it is still unknown if OA affects the migration and invasion of glioma cells. We utilized U-87 MG glioma cell lines and primary glioma cells from patients to study the effect of OA on migration and invasion of glioma cells with multidisciplinary approaches. In this study, we found that OA significantly decreased the ability of glioma cells to migrate and invade. Epithelial-mesenchymal transition (EMT) of glioma cells was also suppressed by OA treatment. Furthermore, MAPK/ERK pathway was greatly inhibited in glioma cells under OA treatment. MAPK/ERK reactivation induced by a recombinant lentiviral vector, Lv-MEK, was able to rescue the inhibitory effect of OA on migration and invasion of glioma cells. Taken together, we provided evidences that OA was a MAPK/ERK pathway-targeting anti-tumor agent. Although the concentrations we used exceeded its physiological level, OA may be used to prevent migration and invasion of glioma cells by developing its derivatives with enhanced bioactivity.
Highlights
Malignant glioma is the most common primary brain tumor with high migration and invasion [1]
We investigated if Oleanolic acid (OA) showed a similar effect on migration and invasion of glioma cells other than U-87 MG
Regarding that Epithelial-mesenchymal transition (EMT) is closely associated with migration and invasion of cancer cells, we subsequently investigated the effect of OA on EMT processes of glioma cells by examining the changes in E-cadherin, N-cadherin, Vimentin and Twist1 expression. Quantitative PCR (qPCR) and immunoblotting assays both demonstrated that the expression of epithelial cell marker, E-cadherin, was elevated in U-87 MG and GT-1# cells under 48 h treatment of 5, 10 and 25 mg/mL (50 mM) of OA in a dose-dependent fashion
Summary
Malignant glioma is the most common primary brain tumor with high migration and invasion [1]. Chemotherapy is one of the most feasible therapeutic modalities for the patients who suffered from glioma invasion. Chemotherapy is always not effective enough in glioma treatment, primarily because most of the existing drugs are not designed for targeting the pathways critical for migration and invasion of glioma cells. It is required to develop specific pathway targeting agents to suppress glioma migration and invasion [2]. Accumulated evidences showed that glioma cells depend on MAPK/ERK signalling pathways to undergo migration and invasion [3,4,5]. Suppression of MAPK/ERK signalling activity compromises migration and invasion ability of glioma cells [6,7,8,9]. MAPK/ERK pathway was believed to be an effective therapeutic target in glioma anti-invasion treatment
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