EXTH-120. Exendin-4 Inhibits BMP4-Dependent Cell Migration and Induces Apoptosis in Glioblastoma

Abstract Glioblastoma (GBM) is an aggressive brain tumor characterized by rapid proliferation, diffuse invasion, and resistance to standard therapies. A key driver of its invasiveness is epithelial–mesenchymal transition (EMT), promoted by bone morphogenetic protein 4 (BMP4), which enhances motility and mesenchymal transformation. High BMP4 expression correlates with increased aggressiveness and poor prognosis. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), originally developed for type 2 diabetes, have shown promise in retrospective studies, with reduced brain tumor incidence observed. However, their mechanistic role in GBM, particularly regarding EMT and BMP4 signaling, remains unclear. This study investigates whether Exendin-4, a GLP-1RA, suppresses GBM cell migration and induces apoptosis via BMP4 and caspase 3/7 pathways. Two patient-derived GBM cell lines from the Mayo Clinic were used: M22 (BMP4-high) and M59 (BMP4-low). Migration was assessed by scratch wound assay after 36-hour Exendin-4 treatment. Proliferation was measured using GFP-based live-cell imaging. Apoptosis was evaluated via Caspase-Glo 3/7 assay. BMP4 expression was analyzed by Western blot at 0, 200, and 400 µM. Exendin-4 reduced migration in both cell lines, with M22 showing sustained 30–50% inhibition at 36 hours (P < 0.05). In M59, inhibition was significant at 12 hours but diminished by 36 hours. Western blot analysis revealed reduced BMP4 protein levels in M22 cells at 400 µM, with no change observed in M59. Proliferation decreased in a dose-dependent manner, with approximately 30% reduction in M22 and 35% in M59 at 400 µM (P < 0.05). Caspase 3/7 activity increased significantly in both lines at 400 µM (M22: 2.6-fold, M59: 3.0-fold; P < 0.01), confirming induction of apoptosis. Exendin-4 significantly impairs key malignant features of glioblastoma by suppressing BMP4-mediated migration, reducing proliferation, and triggering caspase-dependent apoptosis. These results support the therapeutic potential of GLP-1RAs as repurposed agents that target both invasive behavior and cell survival in GBM. Given their clinical safety and mechanistic relevance, GLP-1RAs warrant further investigation as accessible, targeted therapies for high-grade gliomas.