Cyclopeptide moroidin inhibits vasculogenic mimicry formed by glioblastoma cells via regulating β-catenin activation and EMT pathways.

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.