Beyond glucose: alternative sources of energy in glioblastoma

Abstract

Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. With a designation of WHO Grade IV, it is also the most lethal primary brain tumor with a median survival of just 15 months. This is often despite aggressive treatment that includes surgical resection, radiation therapy, and chemotherapy. Based on the poor outcomes and prevalence of the tumor, the demand for innovative therapies continues to represent a pressing issue for clinicians and researchers. In terms of therapies targeting metabolism, the prevalence of the Warburg effect has led to a focus on targeting glucose metabolism to halt tumor progression. While glucose is the dominant source of growth substrate in GBM, a number of unique metabolic pathways are exploited in GBM to meet the increased demand for replication and progression. In this review we aim to explore how metabolites from fatty acid oxidation, the urea cycle, the glutamate-glutamine cycle, and one-carbon metabolism are shunted toward energy producing pathways to meet the high energy demand in GBM. We will also explore how the process of autophagy provides a reservoir of nutrients to support viable tumor cells. By so doing, we aim to establish a foundation of implicated metabolic mechanisms supporting growth and tumorigenesis of GBM within the literature. With the sparse number of therapeutic interventions specifically targeting metabolic pathways in GBM, we hope that this review expands further insight into the development of novel treatment modalities.

Keywords: arginine; autophagy; fatty acids; glioblastoma; glutamine; metabolism.

Figure 1

A representation of the process of fatty acid (beta) oxidation, which takes place within the mitochondrial matrix. Fatty acyl-CoA is initially converted to Δ²-enoyl-CoA, generating one molecule of FADH₂. The Δ²-enoyl-CoA is converted to β-hydroxylacyl-CoA and then β-ketoacyl-CoA, producing an NADH. β-ketoacyl-CoA is then further processed to regenerate a fatty acyl-CoA (now two carbons shorter than when the process of fatty acid oxidation began) and produce an acetyl-CoA. This cyclic shortening repeats until the fatty acid has been completely consumed or, if the fatty acid was composed of an odd number of carbons, until the three-carbon structure propionyl-CoA is all that remains. It is worth noting that the process of fatty acid oxidation does produce any ATP itself, but rather produces metabolites that feed into other metabolic processes. Specifically, the FADH₂ and NADH produced are shunted to the electron transport chain, the generated acetyl-CoA feeds into the tricarboxylic (TCA) cycle, and any propionyl-CoA produced is converted to succinyl-CoA to enter the TCA cycle as well.

Figure 2

Silencing of ASS1 occurs in malignant GBMs through HIF-1α activation or epigenetic mechanisms. This functionally inhibits the urea cycle, shunting key metabolic intermediates toward other pathways. The amino acid arginine can be used in the biosynthesis of nitric oxide to support angiogenesis or can be incorporated in polyamines and proteins to support tumor growth. Additionally, the accumulation of aspartate in ASS1-silenced tumors supports the continued synthesis of pyrimidine nucleotides.

Figure 3

An overview of the pathways through which exogenous glutamine (Gln) is utilized within GBMs. Overexpression of ASCT2 in GBMs leads to enhanced Gln uptake so that it can be used as a substrate in the biosynthesis of nucleotides and proteins. The transport of Gln out of the cell in exchange for excitatory amino acids (EAA) via LAT1 is also upregulated in GBM, leading to enhanced mTOR signaling. Gln can also feed into the TCA cycle via a two-step process that results in the generation of α-KG. During the TCA cycle, a series of reactions converts α-KG into malate. Malate is then further processed to form pyruvate, a reaction which generates NADPH to support growth.