Cycloartobiloxanthone Inhibits Migration and Invasion of Lung Cancer Cells

Abstract

Background/aim: Metastasis in lung cancer is a major cause of high mortality. Metastasis depends on the potential of cancer cells to migrate and invade. Here we demonstrated the anti-migration and invasion activities of the compound cycloartobiloxanthone from Artocarpus gomezianus Wall. ex Tréc. (Moraceae).

Materials and methods: The effect of the compound on viability of human lung cancer H460 cells was investigated by 3-[4,5-dimethylthiazol-2-yl]-2,5diphenyl tetrazoliumbromide (MTT) assay. Migration and invasion assays were performed. Filopodia formation was determined by phalloidin-rhodamine staining. The hallmark signaling proteins in regulation of epithelial to mesenchymal transition (EMT), migration, and integrin α5, αV, β1 and β3 were determined by western blot analysis.

Results: Cycloartobiloxanthone at concentrations lower than 10 μM has no cytotoxic effects. Regarding cell motility, cycloartobiloxanthone at 5-10 μM and 1-10 μM exhibited anti-migration and anti-invasion activities, respectively. Filopodia were found to be significantly reduced in cycloartobiloxanthone-treated cells. These effects correlated with the results from western blot analysis showing that the phosphorylation of focal adhesion kinase on Try397 (p-FAK (Try397)), and cell division cycle 42 (CDC42) were significantly reduced. Cycloartobiloxanthone significantly suppressed migratory integrins including integrin α5, αV, and β3, while had no significant effect on integrin β1. Besides, the compound suppressed epithelial to mesenchymal transition in lung cancer H460 cells indicated by the change in cell morphology form fibroblast-like to epithelial morphology with up-regulation of E-cadherin.

Conclusion: Cycloartobiloxanthone possesses anti-migration and anti-invasion properties by suppressing several migratory-regulated mechanisms including suppressing migratory FAK and CDC42 signal, reduced filopodia of migrating cells, decreasing integrin α5, αv and β3, and inhibiting EMT. Our findings demonstrated the potentials of cycloartobiloxanthone for further studies and developments.

Keywords: Akt; Cycloartobiloxanthone; integrin; invasion; lung cancer; migration.