A role for GLUT3 in glioblastoma cell invasion that is not recapitulated by GLUT1

Abstract

The multifaceted roles of metabolism in invasion have been investigated across many cancers. The brain tumor glioblastoma (GBM) is a highly invasive and metabolically plastic tumor with an inevitable recurrence. The neuronal glucose transporter 3 (GLUT3) was previously reported to correlate with poor glioma patient survival and be upregulated in GBM cells to promote therapeutic resistance and survival under restricted glucose conditions. It has been suggested that the increased glucose uptake mediated by GLUT3 elevation promotes survival of circulating tumor cells to facilitate metastasis. Here we suggest a more direct role for GLUT3 in promoting invasion that is not dependent upon changes in cell survival or metabolism. Analysis of glioma datasets demonstrated that GLUT3, but not GLUT1, expression was elevated in invasive disease. In human xenograft derived GBM cells, GLUT3, but not GLUT1, elevation significantly increased invasion in transwell assays, but not growth or migration. Further, there were no changes in glycolytic metabolism that correlated with invasive phenotypes. We identified the GLUT3 C-terminus as mediating invasion: substituting the C-terminus of GLUT1 for that of GLUT3 reduced invasion. RNA-seq analysis indicated changes in extracellular matrix organization in GLUT3 overexpressing cells, including upregulation of osteopontin. Together, our data suggest a role for GLUT3 in increasing tumor cell invasion that is not recapitulated by GLUT1, is separate from its role in metabolism and survival as a glucose transporter, and is likely broadly applicable since GLUT3 expression correlates with metastasis in many solid tumors.

Targeting Acid Ceramidase Inhibits Glioblastoma Cell Migration through Decreased AKT Signaling

“…To determine the effect of ASAH1 on GBM cell migration, we utilized ASAH1-targeted shRNA and analyzed migration in Boyden chamber assays ( Figure 3 A) using D456 GBM cells isolated from the patient-derived xenograft (PDX). The D456 cells represent the proneural subtype of GBM, and we previously demonstrated their invasive properties [ 35 ]. ASAH1 mRNA was significantly decreased when cells were transduced with lentivirus expressing ASAH1-directed shRNA ( Figure 3 B).…”

NAPRT Expression Regulation Mechanisms: Novel Functions Predicted by a Bioinformatics Approach

“…It represses SLC2A3 (GLUT3), a glucose membrane transporter, which is mostly known for its specific expression in neurons. Very recently, GLUT3’s role in glioblastoma has been described [ 59 ].…”

Noncoding RNAs in the Glycolysis of Ovarian Cancer

“…P53 can inhibit GLUT1 expression in cells, resulting in decreased glucose uptake and thus inhibiting tumor development ( Feng et al, 2018 ). GLUT3 is expressed in most cancer cells but rarely in normal cells, facilitating glucose consumption ( Cazzato et al, 2021 ; Libby et al, 2021 ). Targeting GLUT can inhibit the degree of aerobic glycolysis, affecting tumorigenesis ( Fu et al, 2021 ; Kim E et al, 2021 ).…”