Abstract 2872: GLUT3 promotes metabolic plasticity that drives radiation resistance in glioblastoma

Abstract

Abstract Glioblastomas (GBM) are the most common and malignant brain tumors in adults. While radiation therapy (RT) offers a significant advantage for GBM patients, improving long-term survival remains elusive largely due to the remarkable resistant nature of these tumors. We have shown that metabolic plasticity, especially rewiring of glucose metabolism, promotes radiation survival in GBM. In this study, we investigate the role of glucose transporter 3 (GLUT3) translocation to the cell surface in radiation resistance of GBM. The effect of radiation on GLUT3 total protein levels was determined in patient-derived gliomaspheres via westerns blots, while cellular localization of GLUT3 was determined via immunofluorescence, flow cytometry and cell fractionation assays. The role of the AMPK and αvβ3 integrin in the radiation-induced GLUT3 translocation to the cell membrane was probed via small molecule inhibitors and activators. To determine the role of GLUT3 in radiation survival, GLUT3 levels were knocked down via siRNA and shRNA, followed by functional in vitro and in vivo assays. We provide evidence that irradiated gliomaspheres translocate GLUT3 to the plasma membrane, in a radiation-induced oxidative stress-dependent manner, effectively increasing their glucose uptake and promoting radiation survival. Our data also suggest that GLUT3 translocation to the cell surface contributes to RT resistance. AMPK and αvβ3 integrin are linked to radiation-induced translocation of GLUT3 to the cell membrane, suggesting that targeting these pathways is a potential approach to sensitize GBM tumors to radiation therapy. Citation Format: Lobna Abdulrahman, Justine Bailleul, Hanna Hoang, Aaron Tang, Erina Vlashi. GLUT3 promotes metabolic plasticity that drives radiation resistance in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2872.