Bioenergetic alteration in gastrointestinal cancers: The good, the bad and the ugly

Figure 2 The complex interplay between glycolysis and oxidative phosphorylation in cancer cells. This figure highlights the signaling networks and metabolic regulation in both Warburg-like and oxidative cancer cells. p53 induces PTEN and represses PI3K activity, which inhibits glycolysis and opposes the Warburg effect. Hypoxia and the subsequent activation of hypoxia-inducible factor 1 (HIF-1) play a crucial role in modulating various aspects of cancer cell metabolism, including glycolysis, lactate production, and the tricarboxylic acid (TCA) cycle. Hypoxia counteracts the degradation of HIF-1 by prolyl hydroxylases and von Hippel-Lindau, which stabilizes and activates HIF-1. HIF-1 then transcriptionally activates genes such as hexokinase, phosphofructokinase-1, aldolase A, PGK1, PGAM1, ENO1, and LDHA, as indicated by the red arrows. During glycolysis, excessive lactate can be exported to the extracellular environment, leading to microenvironmental changes such as a lower pH. Intracellular lactate can also be transferred to adjacent cells and re-converted to pyruvate, which can enter the TCA cycle and drive oxidative phosphorylation in oxidative cancer cells. GLUT: Glucose transporter; HK: Hexokinase; G6P: Glucose-6-phosphate; G6PI: Glucose-6-phosphate isomerase; F6P: Fructose-6-phosphate; NADPH: Nicotinamide adenine dinucleotide phosphate; PFK1: Phosphofructokinase-1; F2,6BP: Fructose-2,6-bisphosphate; PFKBP3: Fructose-2,6-biphosphatase 3; F1,6BP: Fructose-1,6-bisphosphate; G3P: Glyceraldehyde-3-phosphate; DHAP: Dihydroxyacetone phosphate; GAPDH: Glyceraldehyde 3-phosphate dehydrogenase; 1,3BPG: 1,3-bisphosphoglycerate; 3PG: 3-phosphoglycerate; PGK: Phosphoglycerate kinase; PGAM: Phosphoglycerate mutase; 2PG: 2-phosphoglycerate; ENO: Enolase; PEP: Phosphoenolpyruvate; PKM1/2: Pyruvate kinase isozyme M1/M2; LDH: Lactate dehydrogenase; MCT: Monocarboxylate transporter family; PDH: Pyruvate dehydrogenase; IDH: Isocitrate dehydrogenase; α-KG: α-ketoglutarate; OAA: Oxaloacetate; SDH: Succinate dehydrogenase; FH: Fumarate hydratase; I: Mitochondrial complex I; II: Mitochondrial complex II; III: Mitochondrial complex III; IV: Mitochondrial complex IV; V: Mitochondrial complex V; Q: Co-enzyme Q; cyto C: Cytochrome c; HIF-1: Hypoxia-inducible factor 1; PHD: Prolyl hydroxylases; VHL: Von Hippel-Lindau.