Metabolic Reprogramming in Glioblastoma Multiforme: A Review of Pathways and Therapeutic Targets

Abstract

Glioblastoma (GBM) is an aggressive and highly malignant primary brain tumor characterized by rapid growth and a poor prognosis for patients. Despite advancements in treatment, the median survival time for GBM patients remains low. One of the crucial challenges in understanding and treating GBMs involves its remarkable cellular heterogeneity and adaptability. Central to the survival and proliferation of GBM cells is their ability to undergo metabolic reprogramming. Metabolic reprogramming is a process that allows cancer cells to alter their metabolism to meet the increased demands of rapid growth and to survive in the often oxygen- and nutrient-deficient tumor microenvironment. These changes in metabolism include the Warburg effect, alterations in several key metabolic pathways including glutamine metabolism, fatty acid synthesis, and the tricarboxylic acid (TCA) cycle, increased uptake and utilization of glutamine, and more. Despite the complexity and adaptability of GBM metabolism, a deeper understanding of its metabolic reprogramming offers hope for developing more effective therapeutic interventions against GBMs.

Keywords: Warburg effect; glioblastoma multiforme; glycolysis; metabolic reprogramming; therapeutic drugs; tumor microenvironment.

Figure 1

The alteration of glycolysis and the PPP in GBM. In healthy cells, oxidative phosphorylation is the dominant pathway, resulting in higher ATP production and low intercellular lactate concentrations. In tumor cells, a phenomenon called the Warburg effect highlights the preference of tumor cells to take up increased amounts of glucose and produce lactate regardless of the presence of oxygen (aerobic glycolysis). The PPP in normal cells operates at a homeostatic rate, utilizing glucose to produce compounds important for nucleotide and amino acid creation. In GBM tumor cells, the pathway is excessively active, producing nucleotide precursors that are useful downstream mechanisms for increasing the size and number of tumor cells. The rewiring of glycolysis and the PPP combined are critical to the survival and further proliferation of cancer cells. ATP, adenosine triphosphate; GBM, glioblastoma multiforme; PPP, pentose phosphate pathway.

Figure 2

Modification of the TCA cycle by GBM tumor cells. The majority of alterations of the TCA cycle consist of modifying concentrations of 3 metabolites: acetyl-CoA, α-ketoglutarate, and succinyl-CoA. In general, branched chain amino acid (e.g., leucine, isoleucine, and valine) are catabolized at higher rates into the different intermediates of the TCA cycle illustrated in the figure. LAT1 is observed in higher levels, which is then converted into BCAAs, which then leads to an increase in levels of acetyl-CoA. Citrate is also used for conversion into acetyl-CoA, supporting the creation of saturated fatty acids. Glutamine, causing a reliance of GBM on glutaminolysis, is catabolized to α-ketoglutarate, which leads to increased production of NADH and FADH2, which feed into the ETC. Conversely, IDH is downregulated in cases of GBM with IDH mutations due to accumulation of 2-HG. Overall, increased metabolites are proposed to cause altered epigenetic regulation that increases tumor proliferation. There are several therapeutics that are under current investigation to work against the metabolic reprogramming that occurs in the TCA cycle of GBM tumor cells. ETC inhibitors work to inhibit an element of ETC (e.g., complex I, complex II, complex III, ATP synthase), thereby reducing the ATP levels in the tumor cells and eventually resulting in cell death. Devimistat is a drug that targets α-ketoglutarate dehydrogenase and is shown to reduce TCA-cycle metabolites, reduce 2-HG, and induce cell death. Glutaminase inhibitors are another form of treatment that work to reduce levels of α-ketoglutarate and 2-HG. The reduction in α-ketoglutarate is thought to be a way to reduce tumor growth. TCA, tricarboxylic acid cycle; CoA, coenzyme A; LAT1, L-type amino acid transporter 1; BCAA, branched chain amino acid; GBM, glioblastoma multiforme; NADH, nicotinamide adenine dinucleotide + hydrogen; FADH, flavin adenine dinucleotide + hydrogen; ETC, electron transport chain; IDH, isocitrate dehydrogenase; 2-HG, 2-hydroxyglutarate; ATP, adenosine triphosphate; ADP, adenosine diphosphate.

Figure 3

Molecular pathways altered by the onset of hypoxia in a malignant glioblastoma cell. When oxygen levels are low in a cell, HIF-1α is stabilized, allowing the transcription factor to translocate to the nucleus before proteasomal degradation. Once in the nucleus, HIF-1α assembles with HIF-1β on the HRE to then enhance transcription of HIF target genes to promote tumorigenesis by increasing cell vascularization; PDGF, VEGF, and TGF. Furthermore, the HIF-1 heterodimer has been linked to increases in the expression of glutamine transporters—enabling higher rates of glutaminolysis—and the upregulation of several glycolytic enzymes and transporters, resulting in increased lactate production. As shown, HIF-1α promotes the expression of PDK1, which decreases the activity of PDH and increases pyruvate availability for lactate production. This is coupled with the increased expression of LDHA. Lastly, while there has been no elucidation of the mechanism, there is a low concentration of BCAAs in hypoxic conditions relative to neighboring normoxic areas. HIF-1α, hypoxia inducible factor-1α; HIF-1β, hypoxia inducible factor-1β; HRE, hypoxia response element; PDGF, platelet-derived growth factor; VEGF, vascular endothelial growth factor; TGF, transforming growth factor; PDK1, pyruvate dehydrogenase kinase 1; PDH, pyruvate dehydrogenase; LDHA, lactate dehydrogenase A; BCCAs, branched chain amino acids.