The role of glucose metabolism and glucose-associated signalling in cancer

Abstract

Aggressive carcinomas ferment glucose to lactate even in the presence of oxygen. This particular metabolism, termed aerobic glycolysis, the glycolytic phenotype, or the Warburg effect, was discovered by Nobel laureate Otto Warburg in the 1920s. Since these times, controversial discussions about the relevance of the fermentation of glucose by tumours took place; however, a majority of cancer researchers considered the Warburg effect as a non-causative epiphenomenon. Recent research demonstrated, that several common oncogenic events favour the expression of the glycolytic phenotype. Moreover, a suppression of the phenotypic features by either substrate limitation, pharmacological intervention, or genetic manipulation was found to mediate potent tumour-suppressive effects. The discovery of the transketolase-like 1 (TKTL1) enzyme in aggressive cancers may deliver a missing link in the interpretation of the Warburg effect. TKTL1-activity could be the basis for a rapid fermentation of glucose in aggressive carcinoma cells via the pentose phosphate pathway, which leads to matrix acidification, invasive growth, and ultimately metastasis. TKTL1 expression in certain non-cancerous tissues correlates with aerobic formation of lactate and rapid fermentation of glucose, which may be required for the prevention of advanced glycation end products and the suppression of reactive oxygen species. There is evidence, that the activity of this enzyme and the Warburg effect can be both protective or destructive for the organism. These results place glucose metabolism to the centre of pathogenesis of several civilisation related diseases and raise concerns about the high glycaemic index of various food components commonly consumed in western diets.

Keywords: TKTL1 transketolase; Warburg effect; cancer; glucose metabolism; pentose phosphate pathway; western diet.

Figure 1.

Schematic illustration of different pathways of glucose metabolism in cancer cells. Glucose enters the cell via glucose transporter proteins (GLUT). Metabolic flux rates in different pathways are determined by the regulation of rate-limiting enzymes as described in the text, as well as by the balanced equilibrium of respective intermediates. Enzymes, reactions, and intermediates of the Embden-Meyerhof pathway are coloured in red, whereas those of the PPP are coloured in blue. Selected enzymes which are referred to in the text are listed at their respective positions. The oxidative branch of the PPP delivers ribose-5-phosphate for the biosynthesis of nucleotides, as well as NADPH for reductive biosynthesis, for the regulation of the redox state within the cell, and for the detoxification of ROS. Within the illustration of the non-oxidative PPP, C₃, C₇, C₆, and C₄ indicate sugar phosphate intermediates, which are interconverted in equilibrium reactions by the transketolase and transaldolase enzymes. Xylulose-5-phosphate, the concentration of which determines the flux rates through both major pathways, may be generated from glucose-6-phosphate via the oxidative or the non-oxidative branch of the PPP. It may serve as a substrate for TKTL1 in a putative cleavage reaction, which generates GAP and a 2-carbon unit, probably acetyl-CoA. Cytosolic acetyl-CoA is utilized for glucose-induced lipogenesis. GAP, which is also generated in the Embden-Meyerhof pathway, may be further metabolized either in the Embden-Meyerhof pathway, or via methylglyoxal to D-lactate. In cancer cells, the generation of L-lactate from pyruvate is predominantly catalyzed by LDHA. Both lactate stereo-isomers are in an equilibrium with pyruvate. Since the oxidation of pyruvate is frequently inhibited in cancer cells (see text), high amounts of lactate are exported via monocarboxylate transporters (MCT).

Figure 2.

The HIF-1 network. The heterodimeric transcription factor HIF-1 consists of a β-subunit (HIF-1β), which is constitutively expressed, as well as an α-subunit (HIF-1α), the expression and stability of which is tightly regulated. Destabilizing factors for HIF-1α are indicated in red colour, whereas stabilizing factors are indicated in blue colour. Translation of HIF-1α is enhanced by the activity of mTORC1 and its downstream activities, which provides a link of HIF-1 activity to survival pathways. The proteolytic degradation of HIF-1α is mediated by the proteasome subsequent to ubiquitylation mediated by the von Hippel-Lindau (VHL)-protein. The recognition of HIF-1α is dependent on the hydroxylation of prolyl residues, which is catalyzed by HIF-1 prolyl hydroxylases 1–3 (HPH). The activity of HPH is a function of the oxygen tension within the cell. HIF-1α is stabilized by hypoxia as well as by several other factors which reflect a loss of metabolic activity in the mitochondria. HIF-1 transactivates a variety of genes which contribute to the hallmarks of aggressive cancer. Notably, at least one of the HIF-1 target genes, PDK1, directly represses the TCA and OXPHOS by the inhibition of PDC.

Figure 3.

Signalling events which determine glucose utilization within the cell. The PI3K-AKT-mTOR-pathway promotes the glycolytic phenotype at various sites via the direct modulation of target proteins as well as on the transcriptional and translational level (for review see Thompson and Thompson, 2004; Sabatini, 2006). One key event supporting aerobic glycolysis is the elevated translation of HIF-1α, the effects of which are illustrated in Figure 2 and discussed in the text. Mitochondrial ROS activate the PI3K-AKT-mTOR-pathway via redox-mediated inhibition of PTEN. Active AMPK and rapamycin negatively regulate PI3K-signalling via suppression of mTORC1. Active AMPK also regulates a glucose-dependent cell cycle checkpoint via phosphorylation of p53. Intact p53 can further directly regulate both glycolysis and OXPHOS via transactivation of its target genes TIGAR and SCO2. Intracellular proteins conferring a suppressive effect on PI3K signalling are indicated in dark blue colour, whereas those which promote this pathway and enable the glycolytic phenotype are indicated in light blue colour.