Epithelial-mesenchymal transition (EMT) is considered as the most important mechanism that underlies the initiation of cancer metastasis. Here we report that the naturally existing flavonoid, hispidulin is capable of preventing human colorectal cancer cells from hypoxia-induced EMT. The treatment of the cells with hispidulin reversed the EMT-related phenotype that has the morphological changes, down-regulation of E-cadherin, and hypoxia-induced cell migration and invasion. The effect was mediated at least in part by inhibiting the mRNA and protein expressions of HIF-1α via modulation of PTEN/PI3K/Akt pathway. In addition, we found that hispidulin-mediated prevention of the E-cadherin down-regulation and cell motility involved blockade of the hypoxia-induced up-regulation of Snail, Slug and Twist. Hispidulin was also effective in increasing expression of E-cadherin mRNA in HT29 colorectal cancer xenografts implanted in the nude mice. In summary, this study showed that hispidulin can prevent EMT induced by hypoxia, the environment that commonly exists in the center of a solid tumor. Given the low toxicity of hispidulin to the healthy tissues, our study suggests that hispidulin can serve as a safe therapeutic agent for suppressing cancer metastasis.
Keywords: EMT; Hispidulin; Hypoxia; PI3K/Akt; PTEN.