Therapeutic Drug-Induced Metabolic Reprogramming in Glioblastoma

Abstract

Glioblastoma WHO IV (GBM), the most common primary brain tumor in adults, is a heterogenous malignancy that displays a reprogrammed metabolism with various fuel sources at its disposal. Tumor cells primarily appear to consume glucose to entertain their anabolic and catabolic metabolism. While less effective for energy production, aerobic glycolysis (Warburg effect) is an effective means to drive biosynthesis of critical molecules required for relentless growth and resistance to cell death. Targeting the Warburg effect may be an effective venue for cancer treatment. However, past and recent evidence highlight that this approach may be limited in scope because GBM cells possess metabolic plasticity that allows them to harness other substrates, which include but are not limited to, fatty acids, amino acids, lactate, and acetate. Here, we review recent key findings in the literature that highlight that GBM cells substantially reprogram their metabolism upon therapy. These studies suggest that blocking glycolysis will yield a concomitant reactivation of oxidative energy pathways and most dominantly beta-oxidation of fatty acids.

Keywords: TCA cycle; glioblastoma; glycolysis; metabolism; oxidative phosphorylation (OXPHOS).

Figure 1

Glycolysis and related pathways in GBM cells. Glucose enters GBM cells via GLUT1 in a manner independent of insulin. Upon entry, glucose is phosphorylated to glucose-6-phosphate and may be processed further in the pentose phosphate pathway or in glycolysis. Glycolysis feeds and communicates with the hexosamine biosynthesis pathway (at the level of fructose-6-phosphate) as well as the serine/glycine pathway (originating from 3-phospho-glycerate). The final product of glycolysis is pyruvate, which may subsequently convert to lactate, resulting in regeneration of NADH to NAD, facilitating rapid glycolytic flux. Lactate is removed from the cell through either MCT1 or MCT4. Alternatively, pyruvate is converted to acetyl-CoA, which in turn reacts to citrate. Citrate may be either processed in the TCA-cycle or used to give rise to cytosolic acetyl-CoA, which is used for fatty acid synthesis. HDAC and aurora kinase A inhibitors block glycolysis by suppression of GLUT1, hexokinase II, and LDHA.

Figure 2

The tricarboxylic acid cycle is fueled by several major sources including glucose, glutamine, and palmitic acid. During glycolysis, glucose (containing six carbons) reacts to 2 molecules of pyruvate. Pyruvate reacts either to oxaloacetate (pyruvate carboxylase reaction) or is oxidized to acetyl-CoA. Acetyl-CoA reacts with oxaloacetate to citrate. Palmitic acid (U-C13) is oxidized (beta-oxidation) and the final product is acetyl-CoA as well. It is noteworthy that both uniformly labeled glucose and palmitic acid result in the m+2 citrate isotopologue (originating from m+2 acetyl-CoA). The carboxylation reaction (pyruvate to oxaloacetate) results in m+3 labeled citrate (not shown). U-13C-Glutamine gives rise to the m+5 alpha-ketoglutarate isotopologue (anaplerotic reaction) and in turn is oxidized in the TCA-cycle. HDAC, aurora kinase A, MET inhibitors, and temozolomide facilitate beta oxidation, enhance anaplerosis through the pyruvate carboxylase reaction, and dampen glutamine oxidation.

Figure 3

Lactic acid is a substrate of the TCA-cycle and involved in acetyl-CoA production. GBM cells take up lactic acid through the membranous transporter MCT1 and convert it to pyruvic acid. Pyruvic acid is subjected to oxidative decarboxylation by PDHA1, resulting in the release of CO₂ and production of acetyl-CoA. Acetyl-CoA is converted into citrate in the TCA cycle and released to the cytosol. The ACLY reaction produces acetyl-CoA that in turn serves as a substrate for histone acetyltransferases that modify histone H3 and H4, resulting in enhanced accessibility of chromatin and transcription of genes facilitating proliferation. CPI613 interferes with lactate metabolism by blocking PDHA and interference with the TCA-cycle. The image is adapted from [23].