Abstract
BackgroundThe conversion of the epithelial phenotype of cancer cells into cells with a mesenchymal phenotype-so-called epithelial–mesenchymal transition (EMT)-has been shown to enhance the capacity of the cells to disseminate throughout the body. EMT is therefore becoming a potential target for anti-cancer drug discovery. Here, we showed that phoyunnanin E, a compound isolated from Dendrobium venustum, possesses anti-migration activity and addressed its mechanism of action.MethodsThe cytotoxic and proliferative effects of phoyunnanin E on human non-small cell lung cancer-derived H460, H292, and A549 cells and human keratinocyte HaCaT cells were investigated by MTT assay. The effect of phoyunnanin E on EMT was evaluated by determining the colony formation and EMT markers. The migration and invasion of H460, H292, A549 and HaCaT cells was evaluated by wound healing assay and transwell invasion assay, respectively. EMT markers, integrins and migration-associated proteins were examined by western blot analysis.ResultsPhoyunnanin E at the concentrations of 5 and 10 μM, which are non-toxic to H460, H292, A549 and HaCaT cells showed good potential to inhibit the migratory activity of three types of human lung cancer cells. The anti-migration effect of phoyunnanin E was shown to relate to the suppressed EMT phenotypes, including growth in anchorage-independent condition, cell motility, and EMT-specific protein markers (N-cadherin, vimentin, slug, and snail). In addition to EMT suppression, we found that phoyunnanin E treatment with 5 and 10 μM could decrease the cellular level of integrin αv and integrin β3, these integrins are frequently up-regulated in highly metastatic tumor cells. We further characterized the regulatory proteins in cell migration and found that the cells treated with phoyunnanin E exhibited a significantly lower level of phosphorylated focal adhesion kinase (p-FAK) and phosphorylated ATP-dependent tyrosine kinase (p-AKT), and their downstream effectors (including Ras-related C3 botulinum (Rac-GTP); Cell division cycle 42 (Cdc42); and Ras homolog gene family, member A (Rho-GTP)) in comparison to those of the non-treated control.ConclusionsWe have determined for the first time that phoyunnanin E could inhibit the motility of lung cancer cells via the suppression of EMT and metastasis-related integrins. This new information could support further development of this compound for anti-metastasis approaches.
Highlights
The conversion of the epithelial phenotype of cancer cells into cells with a mesenchymal phenotypeso-called epithelial–mesenchymal transition (EMT)-has been shown to enhance the capacity of the cells to disseminate throughout the body
Effect of phoyunnanin E on cell viability and proliferation of human lung cancer H460 cells Phoyunnanin E (Fig. 1a) was isolated from D. venustum., and the isolated sample with more than 95% purity was used in this study
To determine the appropriate doses of phoyunnanin E to be used in the following experiments, we evaluated the viabilities of human lung cancer H460 cells treated with phoyunnanin E
Summary
The conversion of the epithelial phenotype of cancer cells into cells with a mesenchymal phenotypeso-called epithelial–mesenchymal transition (EMT)-has been shown to enhance the capacity of the cells to disseminate throughout the body. Integrins consist of alpha and beta subunits, and initiate transmembrane signaling by activating focal adhesion kinase (FAK) and further activate various downstream effectors, such as Protein kinase B (AKT) and the Ras homolog gene family (Rho family) (Cell division cycle 42 (Cdc42), Ras-related C3 botulinum toxin substrate 1 (Rac1), and Ras homolog gene family, member A (RhoA) GTPases), for cancer metastasis [4, 17, 18]. Alterations of these molecules could competently prevent cancer metastasis
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