Geniposide Inhibits Non-Small Cell Lung Cancer by Regulating Proliferation, Apoptosis, Invasion, Migration, Epithelial-Mesenchymal Transition, and Cancer Stem-Like Cell Property Via Wnt/β-Catenin Pathway.

Abstract

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. Geniposide, an active compound of Gardeniae Fructus, has antithrombotic, antitumor, neuroprotective, hepatoprotective, cholestatic, and other effects. The present study aimed to investigate the effects of geniposide on NSCLC cells, as well as its underlying mechanism. Two NSCLC cell lines (H1975 and A549) were treated with different doses of geniposide. The proliferation, apoptosis, migratory and invasive capacities, epithelial-mesenchymal transition (EMT), and stem cell characteristics of NSCLC cells were evaluated using a series of in vitro experiments, including colony formation, flow cytometry, wound healing, transwell, western blotting, and tube formations assays. H1975 cells were subcutaneously injected into nude mice to establish the xenograft tumor models, and the models were intraperitoneally injected with 100 mg/kg geniposide or/and 6 mg/kg SKL2001, an agonist of Wnt pathway. Immunohistochemistry, immunofluorescence, and western blotting analyses of the tumors were performed. Geniposide restrained the proliferation of NSCLC cells, as shown by reduced number of colonies and downregulation of Ki67 and PCNA expression levels. Geniposide promoted apoptosis by reducing Bcl-2 expression and increasing Bax expression. Additionally, geniposide inhibited the migratory and invasive abilities of NSCLC cells as well as reversed the EMT by downregulating vimentin, N-cadherin, snail, and slug and upregulating E-cadherin in the absence or presence of TGF-β1. Furthermore, geniposide attenuated the stem cell characteristics of NSCLC cells. In mechanism, geniposide repressed the activation of Wnt/β-catenin pathway. SKL2001 reversed the anti-NSCLC effects of geniposide in vitro. In the xenograft tumor models, 100 mg/kg geniposide suppressed NSCLC tumor growth, which was reversed by SKL2001 treatment. Overall, geniposide inhibits NSCLC progression by reducing cancer cell proliferation, migration, invasiveness, EMT, and stem cell characteristics. This information might provide novel insights into the potential use of geniposide in lung cancer intervention.