Fisetin suppresses migration, invasion and stem-cell-like phenotype of human non-small cell lung carcinoma cells via attenuation of epithelial to mesenchymal transition

Abstract

Fisetin (3,3′,4′,7-tetrahydroxyflavone) is a bioactive polyphenolic flavonoid found in many fruits and vegetables. It exhibits a variety of pharmacological activities including anticancer and anti-invasive effects. Epithelial to mesenchymal transition (EMT) allows the tumor cells to acquire increased migratory and invasive properties mediating their dissemination to faraway sites, thus favoring metastasis. With metastatic lung cancer claiming the majority of lung cancer-related deaths, agents targeting the pathways underlying metastasis are translationally promising. In the present study, we have explored the anti-metastatic effects of fisetin in non-small cell lung carcinoma (NSCLC) cells A549 and H1299 with emphasis on EMT. The results suggested a significant inhibition in migration and invasion of NSCLC cells under non-cytotoxic concentrations. Furthermore, an attenuation of the EMT was observed in both the cell lines with upregulation in the expression of epithelial marker E-cadherin in A549 cells and ZO-1 in H1299 cells with concomitant downregulation of the mesenchymal markers vimentin as well as N-cadherin along with invasion marker MMP-2. Herein, the downregulation of the expression of NSCLC stem cell signature markers CD44 and CD133 was also observed. Fisetin decreased the expression of multiple signaling proteins (β-catenin, NF-κB, EGFR, STAT-3) acting upstream to EMT and known to be involved in induction and maintenance of mesenchymal phenotype, which may explain the observed effects. Moreover, fisetin decreased the ability of H1299 cells to form colonies on soft agar and potentiated the cytotoxic effects of tyrosine kinase inhibitor (TKI), erlotinib. Overall, our study suggested the ability of fisetin to serve as a potential therapeutic agent on its capacity to attenuate the EMT program and inhibit migration, invasion and stem cell phenotype of lung cancer cells.