Dysregulated metabolic enzymes and metabolic reprogramming in cancer cells

Abstract

Tumor cells carry various genetic and metabolic alterations, which directly contribute to their growth and malignancy. Links between metabolism and cancer are multifaceted. Metabolic reprogramming, such as enhanced aerobic glycolysis, mutations in the tricarboxylic acid (TCA) cycle metabolic enzymes, and dependence on lipid and glutamine metabolism are key characteristics of cancer cells. Understanding these metabolic alterations is crucial for development of novel anti-cancer therapeutic strategies. In the present review, the broad importance of metabolism in tumor biology is discussed, and the current knowledge on dysregulated metabolic enzymes involved in the vital regulatory steps of glycolysis, the TCA cycle, the pentose phosphate pathway, and lipid, amino acid, and mitochondrial metabolism pathways are reviewed.

Keywords: cancer metabolism; glycolysis; lipid metabolism; metabolic enzymes; metabolic reprogramming.

Figure 1.

Glucose metabolism. Glycolysis is the catabolic process in which glucose is broken down to pyruvate via these 10 enzymatic steps. Numerous glycolytic enzymes are altered in cancer cells (purple ovals). GLUT, glucose transporter; HK, hexokinase; PPP, pentose phosphate pathway; PFKFB, 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; PGAM, phosphoglycerate mutase; PK, pyruvate kinase; LDH, lactate dehydrogenase; TCA, tricarboxylic acid cycle.

Figure 2.

Krebs cycle. The TCA is comprised of series of enzyme-catalyzed reactions, located in the mitochondrial matrix. Various enzymes (purple ovals) of the TCA cycle are mutated and/or altered in many types of cancer. TCA, tricarboxylic acid cycle; IDH, isocitrate dehydrogenase; OGDC, oxoglutarate dehydrogenase complex; SCS, succinyl-CoA synthetase; SDH, succinate dehydrogenase; FH, fumarate hydratase; MDH, malate dehydrogenase; CS, citrate synthase.

Figure 3.

PPP, which branches out from glycolysis at the first committed stage of glucose metabolism, is required for nucleotide synthesis in cancer cells. Numerous enzymes of the PPP are associated with various types of cancer. PPP, pentose phosphate pathway; GLUT, glucose transporter; G6PDH, glucose 6-phosphate dehydrogenase; 6PGDH, 6-phosphogluconate dehydrogenase; RuPE, ribulose-5-phosphate-3-epimerase; RPI, ribose-5-phosphate isomerase.

Figure 4.

Essential and non-essential amino acids.

Figure 5.

Lipid metabolism. The interactions between glycolysis, Krebs cycle and lipid metabolism. Lipogenesis is the formation of lipids, whereas lipolysis is the breakdown of lipids. Triglycerides are made up of glycerol and fatty acids. Fatty acids undergo ß-oxidation producing acetyl CoA, which enters the TCA cycle. TCA, tricarboxylic acid cycle; α-KG, α-ketoglutarate.