High Expression of Glycolytic Genes in Clinical Glioblastoma Patients Correlates with Lower Survival

Abstract

Glioblastoma (GBM), the most aggressive brain tumor, is associated with a median survival at diagnosis of 16-20 months and limited treatment options. The key hallmark of GBM is altered tumor metabolism and marked increase in the rate of glycolysis. Aerobic glycolysis along with elevated glucose consumption and lactate production supports rapid cell proliferation and GBM growth. In this study, we examined the gene expression profile of metabolic targets in GBM samples from patients with low grade glioma (LGG) and GBM. We found that gene expression of glycolytic enzymes is up-regulated in GBM samples and significantly associated with an elevated risk for developing GBM. Our findings of clinical outcomes showed that GBM patients with high expression of HK2 and PKM2 in the glycolysis related genes and low expression of genes involved in mitochondrial metabolism-SDHB and COX5A related to tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS), respectively, was associated with poor patient overall survival. Surprisingly, expression levels of genes involved in mitochondrial oxidative metabolism are markedly increased in GBM compared to LGG but was lower compared to normal brain. The fact that in GBM the expression levels of TCA cycle and OXPHOS-related genes are higher than those in LGG patients suggests the metabolic shift in GBM cells when progressing from LGG to GBM. These results are an important step forward in our understanding of the role of metabolic reprogramming in glioma as drivers of the tumor and could be potential prognostic targets in GBM therapies.

PGAM4 silencing inhibited glycolysis and chemoresistance to temozolomide in glioma cells

“…Most tumors, including glioma, primarily metabolize glucose for energy (Strickland & Stoll, 2017). High levels of glycolytic genes associated with lower survival of glioblastoma patients (Stanke et al, 2021). Glycolysis inhibition has been shown to increase the survival of mice with glioblastoma (McKelvey et al, 2021).…”

Oxygen and the Spark of Human Brain Evolution: a Complex Systems Account

“…In light of this evidence, it is not surprising that recent investigations indicate a link between aerobic glycolysis and glioma. High-grade gliomas exhibit the Warburg effect (Cairns et al, 2011;Koppenol et al, 2011), with elevated glycolysis mirroring the rate of tumour proliferation (Vlassenko et al 2015) and a recent report indicating that elevated expression of glycolytic genes corresponds to lower survival in high-grade glioma patients (Stanke et al 2021). Additionally, evidence from a large sample of patients indicates that gliomas tend to occur most commonly in temporal and especially frontal association cortices (Mandal et al, 2020).…”

Heterogeneity of glioblastoma stem cells in the context of the immune microenvironment and geospatial organization

“…Most GBM tumor cells follow the Warburg hypothesis, as evidenced by the overexpression of pyruvate kinase M2 (PKM2) and lactate dehydrogenase, enzymes that plays a key role in glycolysis by directing glucose metabolism towards the production of lactate (169,170). Higher expression of glycolytic genes in GBM results in a more aggressive and lethal phenotype with increased lactate production facilitating biosynthesis of lipids, nucleotides, and macromolecule production, overcoming the reduced availability of nutrients in the TME and supporting tumor cell survival and proliferation (171)(172)(173). Also, GBM cells compete with immune cells for glucose, as activated T cells and NK cells, macrophages, and neutrophils have all been reported to exhibit a metabolic shift towards aerobic glycolysis within the TME, especially during hypoxic conditions, consequently increasing their need for the nutrient (174,175).…”