Metabolism and brain cancer

Abstract

Cellular energy metabolism is one of the main processes affected during the transition from normal to cancer cells, and it is a crucial determinant of cell proliferation or cell death. As a support for rapid proliferation, cancer cells choose to use glycolysis even in the presence of oxygen (Warburg effect) to fuel macromolecules for the synthesis of nucleotides, fatty acids, and amino acids for the accelerated mitosis, rather than fuel the tricarboxylic acid cycle and oxidative phosphorylation. Mitochondria biogenesis is also reprogrammed in cancer cells, and the destiny of those cells is determined by the balance between energy and macromolecule supplies, and the efficiency of buffering of the cumulative radical oxygen species. In glioblastoma, the most frequent and malignant adult brain tumor, a metabolic shift toward aerobic glycolysis is observed, with regulation by well known genes as integrants of oncogenic pathways such as phosphoinositide 3-kinase/protein kinase, MYC, and hypoxia regulated gene as hypoxia induced factor 1. The expression profile of a set of genes coding for glycolysis and the tricarboxylic acid cycle in glioblastoma cases confirms this metabolic switch. An understanding of how the main metabolic pathways are modified by cancer cells and the interactions between oncogenes and tumor suppressor genes with these pathways may enlighten new strategies in cancer therapy. In the present review, the main metabolic pathways are compared in normal and cancer cells, and key regulations by the main oncogenes and tumor suppressor genes are discussed. Potential therapeutic targets of the cancer energetic metabolism are enumerated, highlighting the astrocytomas, the most common brain cancer.

Figure 1

Metabolic differences between normal and cancer cells. Normal cells primarily metabolize glucose to pyruvate for growth and survival, followed by complete oxidation of pyruvate to CO₂ through the TCA cycle and the OXPHOS process in the mitochondria, generating 36 ATPs per glucose. O₂ is essential once it is required as the final acceptor of electrons. When O₂ is limited, pyruvate is metabolized to lactate. Cancer cells convert most glucose to lactate regardless of the availability of O₂ (the Warburg effect), diverting glucose metabolites from energy production to anabolic process to accelerate cell proliferation, at the expense of generating only two ATPs per glucose.

Figure 2

Metabolic remodeling in cancer cells and regulation by signaling pathways involving oncogenes and tumor suppressor genes. The key enzymes of glycolysis, the TCA cycle, the pentose phosphate pathway, glutaminolysis, nucleotide, and lipid biosynthesis are shown as the regulation points by oncogenes and tumor suppressor genes.

Figure 3

Oligonucleotide microarray data of genes coding for key enzymes or subunits of enzymatic complexes of glycolysis and the TCA cycle. Three samples of non-tumoral brain tissues (blue bars) and three samples of GBM (red bars) were submitted to extraction of total RNA and microarray analysis, as described previously., LDHA and PKM2, both enzymes of glycolysis, are upregulated in GBM, whereas the variability in the expression profile of TCA cycle genes suggests that this cycle is uncoupled. The bars represent the median values of the three samples. Numbers represent the normalized fluorescence. Genes coding for glycolysis enzymes: HK2, hexokinase 2; PFK1, phosphofructokinase; PGAM1 and PGAM2, phosphoglycerate mutase 1 and 2, subunits of PGM dimer; PKM2, pyruvate kinase M2; LDHA, lactate dehydrogenase A. Genes coding for the TCA cycle enzymes: PDHA1 and PDHA2, pyruvate dehydrogenase alpha 1 and 2; PDHB, pyruvate dehydrogenase beta; DLAT, dihydrolipoamide-acetyltransferase; DLT, dihydrolipoamide dehydrogenase; PDHX, pyruvate dehydrogenase complex, component X, all six subunits of the enzymatic complex PDH; IDH2, isocitrate dehydrogenase 2; SDHA, SDHB, SDHC, and SDHD, SDH complex, subunits A, B, C, and D; and FUM, fumarate hydratase.