The inhibition of β-catenin activity by luteolin isolated from Paulownia flowers leads to growth arrest and apoptosis in cholangiocarcinoma

Abstract

To develop an inhibitor targeting the Wnt/β-catenin signaling pathway, flavonoid monomer that can interact with β-catenin was isolated from Paulownia flowers. Luteolin may form stable hydrogen bonds with β-catenin by molecular docking. Fluorescence quenching analysis determined the physical interaction between luteolin and β-catenin. The binding of luteolin to β-catenin caused a loss of α-helical structure and induced a conformational change through circular dichroism spectroscopy. Luteolin inhibits the activity of the Wnt signaling, causing cholangiocarcinoma (CCA) cell cycle arrest in the G2/M phase, leading to cell apoptosis and inhibition of cell migration. In addition, transcriptome and proteomics analysis showed that the differentially expressed proteins were significantly enriched in the Wnt/β-catenin pathway. β-catenin protein in the nucleus was significantly decreased, while C-Myc and cyclin D1 in the CCA cells were significantly decreased after luteolin treatment. Additionally, activation of the Wnt/β-catenin signaling reversed the inhibitory effect of luteolin on the migration of CCA cells. Therefore, luteolin can directly interact with β-catenin and act as an inhibitor of β-catenin, inhibiting proliferation and reducing the migration ability of CCA cells by inhibiting the Wnt/β-catenin pathway. This study provides a scientific basis for the development of Wnt/β-catenin pathway inhibitors and the prevention and treatment of CCA.