Research Square · Mar 16, 2026
SGLT2 inhibition suppresses glioblastoma cell proliferation via AMPK activation and mTOR-dependent reduction of protein synthesis under glucose starvation
By Eda T, Takei N, Okada M et al.
Purpose Glioblastoma (GBM) is a malignant brain tumor classified as WHO grade 4, with a median survival of approximately 15 months. Despite multimodal treatment strategies including surgical resection, chemotherapy, and radiotherapy, recurrence is inevitable. This study tested the hypothesis that cancer-specific metabolic profiles could serve as therapeutic targets for GBM, with the aim of developing effective drug therapies. We investigated sodium-dependent glucose transporter 2 (SGLT2) expression on GBM cells and examined the effect of canagliflozin, a selective SGLT2 inhibitor on glucose uptake. In addition, we evaluated the efficacy of canagliflozin on cell proliferation and survival. Finally, the impact of canagliflozin on subcutaneous tumor growth was evaluated using a xenograft model. Methods The effects of SGLT2 inhibition in GBM wereassessed using cultured human GBM cell lines. SGLT2 expression was evaluated by immunoblot analysis. The effect of canagliflozin on intracellular glucose uptake was analyzed using isotope-labeled glucose, with radioactivity quantified by liquid scintillation counting. In vitro responses to canagliflozin were assessed by cell viability, Ki67 proliferation, and apoptosis assays. Changes in signal transduction were examined by immunoblot analysis, focusing on AMPK activation and mTORC1 inhibition. Global protein synthesis was monitored by the SUnSET (surface sensing of translation) method. In mice xenografted with NGT41 cells, patient-derived GBM cell lines, canagliflozin was administered for 10 days, and in vivo responses were evaluated by measuring tumor volume. Results SGLT2 expression was detected in GBM cell lines. In NGT41 cells, canagliflozin dose-dependently inhibited intracellular glucose uptake. Canagliflozin also suppressed cell growth, accompanied by a reduction in proliferating cells and an increase in apoptotic cells. Immunoblot analysis demonstrated the activation of AMPK and inhibition of mTORC1 signaling following canagliflozin treatment. Protein synthesis activity during glucose starvation was reduced by canagliflozin. Administration of canagliflozin significantly reduced tumor volume in vivo and decreased the number of Ki67-positive cells in tissue sections. Conclusions This study demonstrates that the SGLT2 inhibitor canagliflozin induces a glucose starvation in GBM cells, leading to suppression of proliferation. Targeting glucose metabolism via SGLT2 inhibition may represent a promising therapeutic strategy for GBM.