Abstract

Glioblastoma multiforme (GBM) is the most aggressive and deadly brain tumor, portending a median 13-month survival even following gross total resection with adjuvant chemotherapy and radiotherapy. This prognosis necessitates improved therapies for the disease. A target of interest for novel chemotherapies is the Warburg Effect, which describes the tumor’s shift away from oxidative phosphorylation towards glycolysis. Here, we elucidate GLUT1 (Glucose transporter 1) and one of its associated binding partners, TUBB4 (Tubulin 4), as potentially druggable targets in GBM. Using data mining approach, we demonstrate that GLUT1 is overexpressed as a function of tumor grade in astrocytoma’s and that its overexpression is associated with poorer prognosis. Using both mass spectrometry performed on hGBM (human glioblastoma patient specimen) and in silico modeling, we show that GLUT1 interacts with TUBB4, and more accurately demonstrates GLUT1’s binding with fasentin. Proximity ligation assay (PLA) and immunoprecipitation studies confirm GLUT1 interaction with TUBB4. Treatment of GSC33 and GSC28 cells with TUBB4 inhibitor, CR-42-24, reduces the expression of GLUT1 however, TUBB4 expression is unaltered upon fasentin treatment. Using human pluripotent stem cell antibody array, we demonstrate reduced levels of Oct3/4, Nanog, Sox2, Sox17, Snail and VEGFR2 (Vascular endothelial growth factor receptor 2) upon CR-42-24 treatment. Overall, our data confirm that silencing TUBB4 or GLUT1 reduce GSC tumorsphere formation, self-renewal and proliferation in vitro. These findings suggest GLUT1 and its binding partner TUBB4 as druggable targets that warrant further investigation in GBM.

Highlights

  • Glioblastoma (GBM) is a WHO (World Health Organization) Grade IV diffuse glioma with a9.8% 5-year survival rate

  • GLUT1 is Overexpressed in human glioblastoma (hGBM) and Negatively Correlates with Patient Prognosis

  • Increased levels of GLUT1 have been demonstrated in GBM and its inhibition has been shown to increase the effectiveness of temozolomide, a current standard of care in GBM [35]

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Summary

Introduction

Glioblastoma (GBM) is a WHO (World Health Organization) Grade IV diffuse glioma with a9.8% 5-year survival rate. Given the standard of care, that include gross total resection with adjuvant radiation and chemotherapy, the prognosis still necessitates for better treatment options for patients with the devastating astrocytic tumor [1]. Treatment of GBM is difficult because of its intrinsic heterogeneity, both at the cellular and the molecular levels. Recent investigations revealed the existence of glioblastoma stem cells (GSCs), responsible for tumor initiation and maintenance, ensnare GSCs as significant targets to develop novel therapeutics for glioblastoma [2]. This underscores a critical need to identify avenues and distinguish new targets for creating compelling strategies against GBM.

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