Beyond the Warburg Effect: Oxidative and Glycolytic Phenotypes Coexist within the Metabolic Heterogeneity of Glioblastoma

Abstract

Glioblastoma (GBM) is the most aggressive primary brain tumor, with a median survival at diagnosis of 16–20 months. Metabolism represents a new attractive therapeutic target; however, due to high intratumoral heterogeneity, the application of metabolic drugs in GBM is challenging. We characterized the basal bioenergetic metabolism and antiproliferative potential of metformin (MF), dichloroacetate (DCA), sodium oxamate (SOD) and diazo-5-oxo-L-norleucine (DON) in three distinct glioma stem cells (GSCs) (GBM18, GBM27, GBM38), as well as U87MG. GBM27, a highly oxidative cell line, was the most resistant to all treatments, except DON. GBM18 and GBM38, Warburg-like GSCs, were sensitive to MF and DCA, respectively. Resistance to DON was not correlated with basal metabolic phenotypes. In combinatory experiments, radiomimetic bleomycin exhibited therapeutically relevant synergistic effects with MF, DCA and DON in GBM27 and DON in all other cell lines. MF and DCA shifted the metabolism of treated cells towards glycolysis or oxidation, respectively. DON consistently decreased total ATP production. Our study highlights the need for a better characterization of GBM from a metabolic perspective. Metabolic therapy should focus on both glycolytic and oxidative subpopulations of GSCs.

Glycolysis and Fatty Acid Oxidation Inhibition Improves Survival in Glioblastoma

“…Contrary to a recent report by Duraj and colleagues (27), we show that glucose and FAO metabolic pathways are similar among GBM subtypes, and enzymes of the glycolytic and FAO pathways are upregulated in GBM tumors compared to normal brain tissues. While many therapies aim to target the genetic differences in GBM tumors (e.g., EGFR, IDH, FGFR, and TACC), the inhibition of GBM cellular energetics is a potentially wide ranging approach with impact irrespective of GBM subtype.…”

“…Hierarchical clustering demonstrated that glucose and FAO metabolic pathways did not differ between the classical, mesenchymal, and proneural/neural GBM subtypes, offering a potentially wide-ranging therapeutic avenue (Figure 1A), compared to therapies targeting specific genetic mutations (e.g., EGFR and IDH1). This contrasts a recent report of 498 GBM IDH wildtype tumours which demonstrated increased glycolytic activity in the mesenchymal subtype (27).…”

Molecular Mechanisms of Drug Resistance in Glioblastoma

“…Due to high glucose uptake, it could be possible to used 2-18 F-deoxyglucose with PET as a means of diagnosing and monitoring cancer treatment response. Unfortunately, standard procedures such as PET with 2-18 F-deoxyglucose do not differentiate between high glucose uptake due to increased aerobic glycolysis or oxidative phosphorylation, or low glucose uptake due to compensatory glutaminolysis and necrosis [64]. Different enzymes which are involved in aerobic glycolysis can be used as a target for cancer treatment, for example, fasentin, ritonavir, WZB117, STF-31, as inhibitors of the glucose transporter GLUT1; 3-BrPA, 2-DG, lonidamine as inhibitors of the hexokinase; PFK15, 3PO as inhibitors of 6-phosphofructo-2kinase; OA, TT-232, VK3, VK5 as inhibitors of the M2 isoform of pyruvate kinase; rapamycin as an inhibitor of mTORC1; DCA as a PDK1 inhibitor; NAC as an antioxidant, preventing oxidative stress; hydroxy-chloroquine as an autophagy inhibitor; metformin as an inhibitor of oxidative phosphorylation; and halofuginone as an Akt/mTORC1 inhibitor [65].…”

Altered Metabolism in Glioblastoma: Myeloid-Derived Suppressor Cell (MDSC) Fitness and Tumor-Infiltrating Lymphocyte (TIL) Dysfunction

“…Glycolysis, one of the most primitive mechanisms for energy production, is the primary pathway exploited not only in an oxygen-limiting environment, but also under aerobic conditions by complex and fast-growing cancers, such as GBM. Cancer cells rely on glycolysis for energy production not only under low-oxygen conditions but also in the presence of oxygen, a phenomenon termed the “Warburg effect” [ 6 , 7 ]. The advantage of glycolysis in GBM energy production extends beyond just the initial ATP pathway, serving as a center for the rapid production of cellular energy to supply other anabolic pathways and mechanisms made possible by glycolysis [ 1 ].…”