Glioma‐Initiating Cell Elimination by Metformin Activation of FOXO3 via AMPK

Control of the cancer stem/initiating cell population is considered key to realizing the long‐term survival of glioblastoma patients. Recently, we demonstrated that FOXO3 activation is sufficient to induce differentiation of glioma‐initiating cells having stem‐like properties and inhibit their tumor‐initiating potential. Here we identified metformin, an antidiabetic agent, as a therapeutic activator of FOXO3. Metformin activated FOXO3 and promoted differentiation of such stem‐like glioma‐initiating cells into nontumorigenic cells. Furthermore, metformin promoted FOXO3 activation and differentiation via AMP‐activated protein kinase (AMPK) activation, which was sensitive to extracellular glucose availability. Importantly, transient, systemic administration of metformin depleted the self‐renewing and tumor‐initiating cell population within established tumors, inhibited tumor formation by stem‐like glioma‐initiating cells in the brain, and provided a substantial survival benefit. Our findings demonstrate that targeting glioma‐initiating cells via the AMPK‐FOXO3 axis is a viable therapeutic strategy against glioblastoma, with metformin being the most clinically relevant drug ever reported for targeting of glioma‐initiating cells. Our results also establish a novel, direct link between glucose metabolism and cancer stem/initiating cells. In this study metformin, an antidiabetic agent, is identified as a therapeutic activator of FOXO3. The study demonstrates that targeting glioma‐initiating cells via the AMP‐activated protein kinase‐ FOXO3 axis is a viable therapeutic strategy against glioblastoma, with metformin being the most clinically relevant drug ever reported for targeting of glioma‐initiating cells.