Glioblastoma Metabolism: Insights and Therapeutic Strategies

Abstract

Tumor metabolism is emerging as a potential target for cancer therapies. This new approach holds particular promise for the treatment of glioblastoma, a highly lethal brain tumor that is resistant to conventional treatments, for which improving therapeutic strategies is a major challenge. The presence of glioma stem cells is a critical factor in therapy resistance, thus making it essential to eliminate these cells for the long-term survival of cancer patients. Recent advancements in our understanding of cancer metabolism have shown that glioblastoma metabolism is highly heterogeneous, and that cancer stem cells exhibit specific metabolic traits that support their unique functionality. The objective of this review is to examine the metabolic changes in glioblastoma and investigate the role of specific metabolic processes in tumorigenesis, as well as associated therapeutic approaches, with a particular focus on glioma stem cell populations.

Keywords: cancer stem cells; glioblastoma; metabolism; therapy; tumorigenic processes.

Figure 1

Active metabolic pathways in glioblastoma. Cancer cells exhibit a variety of metabolic changes, including increased glycolysis leading to lactate production and glutaminolysis, which provides energy for the TCA cycle. Metabolic nutrients are highlighted in bold. Metabolic intermediates are channeled into nucleic acid, amino acid, and lipid biosynthetic pathways. These metabolic pathways are intricately connected [10,18]. α-KG: α-Ketoglutarate; ATP: Adenosine Triphosphate; DHAP: Dihydroxyacetone Phosphate; ETC: Electron Transport Chain; FAO: Fatty Acid Oxidation; G3P: Glyceraldehyde-3-Phosphate; OXPHOS: Oxidative Phosphorylation; P: Phosphate; PPP: Pentose Phosphate Pathway; TCA: Tricarboxylic Acid Cycle. Figure created with BioRender.com.

Figure 2

Warburg effect and related therapy. The Warburg effect, a hallmark of cancer metabolism, refers to metabolic reprogramming in cancer cells towards increased glucose uptake, glycolysis, and lactate production, even in the presence of oxygen. The most critical enzymes and transporters involved in this process are highlighted in bold and potential therapies in red. Targeting these enzymes and transporters is a potential strategy in cancer therapy. ADP: Adenosine Diphosphate; ATP: Adenosine Triphosphate; AEO: Anhydrous Enol-Oxaloacetate; 5-ALA: 5-Aminolevulinic Acid; 2-DG: 2-Deoxyglucose; ENO: Enolase; GAPDH: Glyceraldehyde-3-Phosphate Dehydrogenase; GLUT: Glucose Transporter; HK: Hexokinase; LDH: Lactate Dehydrogenase; MCT: Monocarboxylate Transporter; NAD⁺/NADH,H⁺ Oxidized/reduced Nicotinamide Adenine Dinucleotide; NHE1: Sodium-Hydrogen Exchanger 1; PGAM1: Phosphoglycerate Mutase 1; PFK1: Phosphofructokinase-1; PGK1: Phosphoglycerate Kinase 1; PKM2: Pyruvate Kinase M2; TPI: Triosephosphate Isomerase. Figure created with BioRender.com.

Figure 3

Glutamine metabolism pathways and processes in tumorigenesis and related therapy. Reprogrammed glutamine metabolism is involved in tumorigenic processes, which are highlighted in green. Reprogrammed glutamine metabolism supplies essential components for nucleotides, amino acids, and fatty acids biosynthesis, drives the TCA cycle, and maintains redox balance, as well as influencing epigenetic modifications through modulation of α-KG levels. Cancer cells take up glutamine via the transporter ASCT2/SLC1A5, which is then converted into glutamate by glutaminase. The conversion of glutamate to α-ketoglutarate by glutamate dehydrogenase fuels the TCA cycle. In GB, therapeutic targets are highlighted in bold and therapy in red. NADP⁺/NADPH,H⁺: Oxidized/reduced Nicotinamide Adenine Dinucleotide Phosphate; GLS: Glutaminase; GDH1/2: Glutamate Dehydrogenase 1/2; GSH/GSSG: Reduced/oxidized Glutathione; SLC1A5/ASCT2: Solute Carrier Family 1 Member 5/Alanine Serine Cysteine Transporter 2, member 5; TCA: Tricarboxylic Acid Cycle. Figure created with BioRender.com.

Figure 4

Arginine metabolism and related therapies. In glioblastoma, alterations in arginine metabolism are observed, characterized by an increase in arginine uptake, elevated arginase 2 (ARG II) levels, and a decrease in Argininosuccinate Synthase 1 (ASS1), an enzyme responsible for endogenous arginine synthesis. Therapeutic targets for GB are highlighted in bold, and therapies in red. The latter approach has shown promising results in ASS1-deficient glioblastomas. ADI-PEG20: Pegylated Arginine Deaminase; ASS1: Argininosuccinate Synthase 1; ARG: Arginase; ASL: Argininosuccinate Lyase; NO: Nitric Oxide; NOS: Nitric Oxide Synthase; ODC: Ornithine Decarboxylase; OTC: Ornithine Transcarbamylase. Figure created with BioRender.com.

Figure 5

Lipid metabolism and associated therapies. In glioblastoma, alterations occur in multiple lipid biosynthesis and degradation pathways, including de novo lipogenesis, Fatty Acid Oxidation, cholesterol metabolism, and other lipid-related pathways. This figure highlights potential therapeutic targets in lipid metabolism that are highlighted in bold, as well as several therapies that target lipid-associated pathways, which are highlighted in red. ACC: Acetyl-CoA Carboxylase; ACCS2: Acetyl-CoA Synthetase 2; ACAT: Acetyl-CoA Acetyltransferase; α-KG: α-Ketoglutarate; ATP: Adenosine Triphosphate; CPT: Carnitine Palmitoyltransferase; DHAP: Dihydroxyacetone Phosphate; ETC: Electron Transport Chain; EGFR: Epidermal Growth Factor Receptor; ELOVL: Elongation of Very Long Chain Fatty Acids; ER: Endoplasmic Reticulum; FADs: Long-Chain Acyl-CoA Dehydrogenases; FAO: Fatty Acid Oxidation; FAPB7: Fatty Acid Binding Protein 7; FASN: Fatty Acid Synthase; FATP: Fatty Acid Transport Protein; G3P: Glyceraldehyde-3-Phosphate; GPD1: Glycerol-3-Phosphate Dehydrogenase 1; HGF: Hepatocyte Growth Factor; HMG-CoA: Hydroxymethylglutaryl-CoA; HMGCR: Hydroxymethylglutaryl-CoA Reductase; HMGCS: Hydroxymethylglutaryl-CoA Synthase; IDH1: Isocitrate Dehydrogenase 1; MCT: Monocarboxylate Transporters; OXPHOS: Oxidative Phosphorylation; P: Phosphate; PPAR: Peroxisome Proliferator-Activated Receptors; SCAP: SREBP-Cleavage-Activating Protein; SCD: Stearoyl-CoA Desaturase; SREBP-1: Sterol Regulatory Element Binding Proteins; SMPD1: Sphingomyelin Phosphodiesterase 1; SOAT1: Sterol O-Acyltransferase 1; TCA: Tricarboxylic Acid Cycle. Figure created with BioRender.com.

Figure 6

Nucleotide metabolism and associated therapies. This figure highlights potential therapeutic targets in nucleotide metabolism that are highlighted in bold, as well as several therapies that target nucleotide-associated pathways, which are highlighted in red. ADP: Adenosine Diphosphate; AMP: Adenosine Monophosphate; APRT: Adenosine Phosphoribosyltransferase; ATP: Adenosine Tri-phosphate; cAMP: Cyclic Adenosine Monophosphate; CAD: Carbamoyl-Phosphate Synthetase 2, Aspartate Transcarbamylase, and Dihydroorotase; CDP: Cytidine Diphosphate; CMP: Cytidine Monophosphate; CTP: Cytidine Triphosphate; DHODH: Dihydroorotate Dehydrogenase; DNA: Deoxyribonucleic Acid; dFdC: Difluoro-deoxy-cytidine; dFdCDP: Difluoro-deoxy-cytidine Diphosphate; dFdCMP: Difluoro-deoxy-cytidine Monophosphate; dFdCTP: Difluoro-deoxy-cytidine Triphosphate; dFdUMP: Difluoro-deoxy-uridine Monophosphate; dFdU: Difluoro-deoxy-uridine; dUDP: Deoxyuridine Diphosphate; dUMP: Deoxyuridine Monophosphate; GDP: Guanosine Diphosphate; GMP: Guanosine Monophosphate; GTP: Guanosine Triphosphate; HGPRT: Hypoxanthine-Guanine Phosphoribosyltransferase; IMP: Inosine Monophosphate; IMPDH2: Inosine Monophosphate Dehydrogenase 2; MMF: Mycophenolate mofetil; dNTP: Deoxynucleotide Triphosphate; NTP: Nucleotide Triphosphate; OMP: Orotidine Monophosphate; PRPP: Phosphoribosyl Pyrophosphate; TMP: Thymidine Monophosphate; UDP: Uridine Diphosphate; UMP: Uridine Monophosphate; UTP: Uridine Triphosphate; UMPS: Uridine Monophosphate Synthetase.

Figure 7

Advanced metabolic-targeted therapy in glioblastoma. α-KG: α-Ketoglutarate; ARG: Arginase; ATP: Adenosine Triphosphate; DCA: Dichloroacetate; ETC: Electron Transport Chain; FAO: Fatty Acid Oxidation; FASN: Fatty Acid Synthase; HMGCR: Hydroxymethylglutaryl-CoA Reductase; IMPDH: Inosine Monophosphate Dehydrogenase; MPA: Mycophenolic acid; MMF: Mycophenolate mofetil; OXPHOS: Oxidative Phosphorylation; PKM2: Pyruvate Kinase M2; PRMT5: Protein Arginine Methyltransferase 5; TCA: Tricarboxylic Acid Cycle. Figure created with BioRender.com.