Partial Activation of PPAR-γ by Synthesized Quercetin Derivatives Modulates TGF-β1-Induced EMT in Lung Cancer Cells.

Non-small cell lung cancer (NSCLC) has a 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, this group synthesized a series of Schiff base quercetin derivatives (QDs) and ascertained their effectiveness on EMT markers of A549 cell line. This study evidenced that the EMT process is counteracted via the partial activation of a nuclear hormone receptor, Peroxisome proliferator-activated receptor (PPAR)-γ through QDs. Here, that work is extended to investigate the interplay between PPAR-γ partial activation and TGF-β1-induced EMT in human lung cancer A549 cells. The results reveal that TGF-β1 plays a critical role in suppressing PPAR-γ, which is markedly reversed and increased by partial agonists: QUE2FH and QUESH at both protein and transcriptional levels. The partial agonists not only stimulate PPAR-γ in a balanced manner but also prevent the loss of E-cadherin and acquisition of TGF-β1-induced mesenchymal markers (Snail, Slug, Vimentin, and Zeb-1). Subsequently, the effects are accompanied by attenuation of TGF-β1-induced migratory ability of A549 cells.