Abstract
A small subpopulation of tumor stem-like cells has the capacity to initiate tumors and mediate radio- and chemoresistance in diverse cancers hence also in glioblastoma (GBM). It has been reported that this capacity of tumor initiation in the brain is mainly dependent on the body’s nutrient supply. This population of so-called brain tumor initiating or brain tumor stem-like cells (BTSCs) is able to extract nutrients like glucose with a higher affinity. Riluzole, a drug approved for treating amyotrophic lateral sclerosis (ALS), was reported to possess anticancer properties, affecting the glutamate metabolism. We report that riluzole treatment inhibits the growth of brain tumor stem-like cells enriched cultures isolated from two human glioblastomas. The effects of riluzole on these cells were associated with an inhibition of a poor prognostic indicator: glucose transporter 3 (GLUT3). A decrease in GLUT3 is associated with a decrease in the p-Akt/HIF1α pathway. Further, downregulation of the DNA (Cytosine-5-)-methyltransferase 1 (DNMT1) gene that causes hypermethylation of various tumor-suppressor genes and leads to a poor prognosis in GBM, was detected. Two hallmarks of cancer cells—proliferation and cell death—were positively influenced by riluzole treatment. Finally, we observed that riluzole reduced the tumor growth in in vivo CAM assay, suggesting it could be a possible synergistic drug for the treatment of glioblastoma.
Highlights
Metabolic alterations in cancers, which are characterized by cells favoring aerobic glycolysis rather than oxidative phosphorylation, are known as possessing what is called the Warburg effect [1]
We examined the effect of riluzole on the viability of two brain tumor stem-like cell lines: 11SP and 64SP
We evaluated the brain tumor stem-like cells (BTSCs) immunophenotype with CD133, the cell surface marker and Nestin, an intermediate filament protein, known as neural stem and progenitor cell markers (Figure 1A); we looked at their ability to differentiate into the three different neural lineages and to form colonies in soft agar assay (Supplementary Figure 1) and in in vivo chorioallantoic membrane assay (CAM) assay (Figure 5)
Summary
Metabolic alterations in cancers, which are characterized by cells favoring aerobic glycolysis rather than oxidative phosphorylation, are known as possessing what is called the Warburg effect [1]. In glioblastoma (GBM), the most lethal and prevalent primary form of malignant brain tumor, glycolysis was upregulated by as much as threefold compared to a measurement taken from normal brain tissue [2]. As the primary energy source in a normal brain, glucose [3] must be transported across the endothelial cells of the bloodbrain barrier and taken up into the neuronal and glial cells. The GLUT1 (gene: SLC2A1) and GLUT3 (gene: SLC2A3) proteins are significant indicators of a poor prognosis outcome in oral squamous cell carcinoma, probably because of the enhanced glycolytic metabolism of more aggressive neoplastic cells [6]. GLUT3 expression contributes to the proliferation of lung tumor cells and is an independent prognostic factor of poor overall survival in non-small cell lung cancers [8]
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