Abstract
AbstractNon-small cell lung cancer (NSCLC) possess very low survival rate due to poor response to chemotherapy and late detection. Epithelial to mesenchymal transition (EMT) is regarded as a major contributor to drive metastasis during NSCLC progression. Towards this, transforming growth factor-beta 1 (TGF-β1) is the key driver that endows cancer cells with increased aggressiveness. Recently, our group synthesized a series of Schiff base quercetin derivatives (QDs) and ascertained their effectiveness on EMT markers of A549 cell line. Our study evidenced that EMT process was counteracted via the partial activation of a nuclear hormone receptor, Peroxisome proliferator-activated receptor (PPAR)-γ through QDs. Hence, here we extended our work to investigate the interplay between PPAR-γ partial activation by synthesized QDs, TGF-β1-induced EMT and migration in human lung cancer A549 cells. The results revealed that TGF-β1 played a critical role in suppressing PPAR-γ, which was markedly reversed and increased by partial agonists; QUE2FH and QUESH at both protein and transcriptional level. Compared to full agonists, rosiglitazone could not elevate PPAR-γ expression in the presence of TGF-β1 and had negligible effect on translocation of PPAR-γ to nucleus. The partial agonists not only stimulated PPAR-γ in balanced manner but also prevented the loss of E-cadherin and acquisition of TGF-β1-induced mesenchymal markers (Snail, Slug, Vimentin and Zeb-1). Subsequently, the effects were accompanied by attenuation of TGF-β1-induced migratory ability of A549 cells. Together, with the balanced activation profile of PPAR-γ ligands, our findings suggest that these novel partial agonists may serve as potential anti-cancer agents to impede metastasis.
Publisher
Cold Spring Harbor Laboratory