Metformin Suppresses Glioblastoma Tumor Growth and Progression Through the AMPK/FoxO3a/Survivin Axis

Glioblastoma (GB) is one of the most aggressive malignant brain tumors. Due to the high invasiveness of this cancer, surgical removal is often not possible, and relapses after surgery are very common, making current treatments ineffective. Developing new therapies or treatment combinations remains a major challenge in managing GB. Metformin (MET), an anti-diabetic medication, has recently gained attention for its potential anticancer effects. To better understand how MET inhibits GB growth at the molecular level, we studied its impact on survivin, a member of the inhibitor of apoptosis (IAP) family that is essential for GB cell survival, resistance to radio- and chemotherapy, and tumor recurrence. Using T98G and U87-MG cell lines, we performed cell viability, migration, and invasion assays, along with Western blot analysis, ChIP assays, and gene silencing experiments to examine key signaling pathways. We found that MET effectively inhibits the growth, viability, and invasiveness of GB cell lines through a molecular mechanism involving activation of the AMPK/FoxO3a/survivin pathway. In vivo studies support these findings, showing increased FoxO3a and decreased survivin in brain tissue sections from metformin-treated mice compared with untreated controls. These results suggest new possibilities for repurposing MET as an adjuvant treatment for GB.