The Molecular Mechanism Underlying Verticillin A In Suppression Of Colon Cancer Cell Migration

Verticillin A belongs to diketopiperazine compounds, and is isolated from Amanita flavorubescens Alk. (contains parasitic fungi Hypomyces hyalines (Schw.)Tul.). In this study, we first discover Verticillin A has anti tumor metastasis bioactivity. It is well known that tumor cell metastasis is a big obstacle during oncotherapy, and discovering a drug that can inhibit the metastasis of tumor cells will be of great significance. This study explored the molecular mechanism of Verticillin A that inhibits cancer cell migration. Through wound healing assay and Tranwell assay, we observed Verticillin A could effectively inhibit colon cancer cell migration in vitro. We identified c-Met as the molecular target of Verticillin A by screening key genes related to cell migration. Besides, we found that Verticillin A suppressed downsream signaling PI3K-Akt and Ras/Raf-MAPK through c-Met, thus inhibited cancer cell migration. At the molecular level, we identified Verticillin A could actively suppress c-Met phosphorylation motivated by HGF. Utilizing Transwell assay to simulate tumor cell migration process, we also found Veriillin A could effectively reverse cell migration ability amplified by HGF. Verticillin A alone could not obviously inhibit cancer cell migration, but exhibited potent activity against colon cancer cell metastasis while combined with TRAIL in vivo. The molecular mechanism of the drug synergism of Verticillin A is not clear, and need further study.Taken together, Verticillin A was found to actively inhibite the migration ability of colon cancer cells, and target c-Met to further down regulate PI3K-Akt and Ras/Raf-MAPK signaling pathway. We are the first to elucidate the effect of Verticillin A in againsting tumor cell metastasis, and provide the theoretical support for the future development of verticillin A as a promising anti-cancer drug in human colon cancer therapy.