GLUT1 and TUBB4 in Glioblastoma Could be Efficacious Targets

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.

Auditory impairment in H‐ABC tubulinopathy

“…This role becomes even more important when axons spike at higher frequencies. Interestingly, it has been reported that TUBB4A interacts with glucose transporter‐1 (Guda et al, 2019). It should still be proved whether the mutation in TUBB4A in patients with H‐ABC modifies this interaction and if metabolic changes could contribute to the physiopathology of the disease.…”

Dysregulated Alanine as a Potential Predictive Marker of Glioma—An Insight from Untargeted HRMAS-NMR and Machine Learning Data

“…Several research groups have demonstrated that, in order to perform (i) harvesting of energy and replenishing the ‘nutrient (glucose) sink’ for a continuous, unchecked cellular proliferation; (ii) epithelial-to-mesenchymal transition (EMT); (iii) enhanced cell migration; and iv) increased angiogenesis, the cancer cells establish a preference for glycolytic metabolism—a so-called Warburg effect [ 13 , 14 , 15 ]. This metabolic reprogramming/shift from the oxidative phosphorylation to glycolytic pathway coupled with concomitant upregulated expression of the solute carrier 2 (SLC2) family of transporters (e.g., glucose transporter GLUT1, GLUT3, GLUT4) is the central hallmark of malignant gliomas [ 13 , 15 , 16 ]. While on one hand, it exerts a selective pressure for tumor survival in the tumor microenvironment, at the same time, it drastically perturbs the metabolic influx of glucose within the cell cytoplasm and in circulation (more importantly, blood plasma, which is supplying nutrients to the entire body).…”

Purification of Gekko Small Peptide Fraction and Its Effect of Inducing Apoptosis of EC 9706 Esophageal Cancer Cells by Inhibiting PI3K/Akt/GLUT1 Signaling Pathway

“…Even when oxygen is abundant, and mitochondria are functioning, tumor cells obtain energy mainly through glycolysis, a process known as Warburg effect [1,2] . Glucose transporter (GLUT) is the main carrier mediating glucose uptake in cells, regulating glucose transmembrane transport [3] . Therefore, glucose uptake is an important rate‐limiting step in anaerobic fermentation of cancer cells.…”