Koumine from Gelsemium elegans Benth suppresses colorectal cancer metastasis by inhibiting vasculogenic mimicry formation through epithelial-mesenchymal transition and cytoskeleton remodeling

Colorectal cancer (CRC) continues to be a leading cause of cancer-related mortality globally, with metastasis representing a critical determinant to poor prognosis. Vasculogenic mimicry (VM), a non-endothelial tumor microcirculation pattern, promotes tumor aggression and resistance to conventional anti-angiogenic therapies. Epithelial-mesenchymal transition (EMT) and cytoskeletal remodeling are critical for VM formation and metastasis. Koumine (KM), a primary alkaloid from Gelsemium elegans Benth, exhibits anti-tumor properties. This study employed a multidimensional experimental approach to systematically evaluate the inhibitory effects of KM on colorectal cancer metastasis. Our findings demonstrate that KM effectively inhibits multiple metastatic processes in CRC, including cell migration, invasion, and VM formation in vitro and in vivo. Proteomics analysis revealed downregulation of EphA2, a key VM regulator, and enrichment of cytoskeleton-related pathways. KM disrupted actin reorganization, stabilized Vinculin-rich focal adhesions, and suppressed EMT, as evidenced by E-cadherin upregulation couple with downregulation of N-cadherin, Vimentin, Snail. In xenografts models, KM reduced tumor growth, VM and lung metastasis. These effects were accompanied by the downregulation of the EphA2 and FAK. These results suggest that KM may have potential as an adjunctive therapeutic agent for CRC metastasis.