PDF(Pubmed)
Abstract：
Glioblastoma (GBM) is a highly vascularized malignant brain tumor with poor clinical outcomes. Vasculogenic mimicry (VM) formed by aggressive GBM cells is an alternative approach for tumor blood supply and contributes to the failure of anti-angiogenic therapy. To date, there is still a lack of effective drugs that target VM formation in GBM. In the present study, we evaluated the effects of the plant cyclopeptide moroidin on VM formed by GBM cells and investigated its underlying molecular mechanisms. Moroidin significantly suppressed cell migration, tube formation, and the expression levels of α-smooth muscle actin and matrix metalloproteinase-9 in human GBM cell lines at sublethal concentrations. The RNA sequencing data suggested the involvement of the epithelial-mesenchymal transition (EMT) pathway in the mechanism of moroidin. Exposure to moroidin led to a concentration-dependent decrease in the expression levels of the EMT markers N-cadherin and vimentin in GBM cells. Moreover, moroidin significantly reduced the level of phosphorylated extracellular signal-regulated protein kinase (p-ERK) and inhibited the activation of β-catenin. Finally, we demonstrated that the plant cyclopeptide moroidin inhibited VM formation by GBM cells through inhibiting the ERK/β-catenin-mediated EMT. Therefore, our study indicates a potential application of moroidin as an anti-VM agent in the treatment of GBM.
摘要：
胶质母细胞瘤（GBM）是一种高度血管化的恶性脑肿瘤，临床预后较差。由侵袭性GBM细胞形成的血管生成拟态（VM）是肿瘤血液供应的替代方法，并导致抗血管生成治疗（AAT）的失败。然而,目前仍缺乏针对GBM中VM形成的有效药物。在本研究中,我们评估了植物环肽oroidin对GBM细胞形成的VM的影响，并探讨了其潜在的分子机制。莫罗伊丁显然抑制了迁移，在亚致死浓度下，人GBM细胞系中α-SMA和金属蛋白酶9的试管形成和表达。RNA测序数据表明EMT途径参与了莫罗定的机制。将GBM细胞暴露于莫罗定，EMT标记N-Cadherin和波形蛋白的表达呈浓度依赖性下降。此外，horoidin显着降低磷酸化ERK的水平并抑制β-catenin的激活。植物环肽莫罗苷通过抑制ERK/β-catenin介导的EMT来抑制GBM细胞形成的VM。我们的研究表明，在GBM的治疗中，horoidin作为抗VM药物具有良好的应用前景。
