Metabolic reprogramming in tumor cells. The alteration of bioenergetic pathways in tumor cells is evident from their increased glucose uptake (a) through glycolysis (b), the intermediate metabolites of which are also shuttled into biosynthetic pathways (synthesis of nucleic acids from glucose 6-phosphate through the pentose phosphate pathway (c), amino acids from glycerate 3-phosphate (not shown) and lipogenesis from pyruvate (d)) that are necessary for cell growth and proliferation. In tumor cells, pyruvate in the mitochondria is shuttled into a truncated tricarboxylic acid cycle where it is converted to acetyl-CoA by pyruvate dehydrogenase and combined with oxaloacetate for export into the cytosol as citrate for the synthesis of isoprenoids, cholesterol and fatty acids. Open up and down arrows indicate upregulation and downregulation of enzymes, respectively. Enzymes upregulated by activation of HIF-1 are in red. Abbreviations: ACL, adenosine triphosphate citrate lyase; ADP, adenosine diphosphate; ATP, adenosine triphosphate; CA9 and CA12, carbonic anhydrases 9 and 12; CPT1A, carnitine palmitoyltransferase 1A; FASN, fatty acid synthase; G6P, glucose 6-phosphate; GLUT1,3,4, glucose transporter 1, 3 and 4; GSH, glutathione; HIF-1, hypoxia-inducible factor 1; HK1,2, hexokinase1 and 2; LAT1, L-type amino acid transporter 1; LDH-A, lactate dehydrogenase A; MCT4, monocarboxylate transporter 4; M2-PK, pyruvate kinase isoform M2; NAD+, nicotinamide adenine dinucleotide oxidized; NADH, nicotinamide adenine dinucleotide reduced; NADPH, nicotinamide adenine dinucleotide phosphate; NHE1, Na+/H+ exchanger 1; OAA, oxaloacetate; OXPHOS, oxidative phosphorylation; PDH, pyruvate dehydrogenase; PDK1, pyruvate dehydrogenase kinase 1; PFK2, phosphofructokinase 2; PGM, phosphoglycerate mutase; PI3K, phosphatidylinositol 3-kinase; PPP, pentose phosphate pathway; TLK1, transketolase 1; VDAC, voltage-dependent anion channel. Reproduced with permission from .