Pro statu isto translation1/24/2024 Furthermore, tumour cells appear to turn on different programs of metabolic pathways to generate ATP, proteins, nucleotides and lipids for cellular proliferation compared with normal cells. TCA cycle, glycolysis and pentose phosphate pathway) in mammalian systems, and this approach has been instrumental in demonstrating that the metabolism of a tumour depends on factors such as the tissue of origin, the tumour microenvironment (TME), the level of hypoxia, and so on. Advances in nuclear magnetic resonance and mass spectroscopy have helped to quantify the carbon influx of the central metabolic pathways (e.g. Several tools have been designed to assess metabolism without disturbing the system. 6 Although the exact mechanism(s) of altered metabolism and its effect on cancer behaviour is unknown, an increased awareness of the dependencies of cancer cells on specific metabolic pathways and the potential for therapeutically exploiting these dependencies have led to an interest in better understanding the underlying processes. The Warburg effect might support anabolic metabolism indirectly while maintaining large pools of glycolytic intermediates that favour engagement of the pentose phosphate pathway and other biosynthetic pathways inside the cell. 3 This change was originally thought to be due to defective oxidation caused by mitochondrial dysfunction, but has now been partly explained biologically 4, 5: the rapid uptake and metabolism of glucose allows cells to feed several non-mitochondrial pathways, such as the pentose phosphate pathway, which produces ribose for nucleotides and NADPH for reductive biosynthesis, and the hexosamine pathway, which is required for protein glycosylation and glycerol synthesis for production of complex lipids. 1, 2 The Warburg effect, for example, is a change in the metabolism of most cancer cells that enables them to convert glucose into lactate, even in the presence of abundant oxygen-in a process known as aerobic glycolysis. Unlike normal cells, cancer cells rewire their cellular metabolism to promote growth and survival and thus have different nutritional requirements, and many different cancer types exhibit similar metabolic alterations. ROS, mainly generated through NADPH oxidase (NOX4) and through electron leak from electron transport chain (ETC) complexes, are potent mitogens that promote proliferation, differentiation and migration. Ammonia, generated as a by-product of proteins that are broken into amino acids by amino acid lyases and nucleotide deaminases, is toxic at high concentrations and, thus, gets further converted into urea. For many years, lactate was seen as the metabolic waste product of glycolytic metabolism however, new roles for lactate in the tumour microenvironment as a metabolic fuel, modulator of extracellular pH or as a signalling molecule have emerged. Emerging studies have revealed a functional role for many of these metabolic by-products. Cells also produce lactate, ammonia, carbon dioxide and reactive oxygen species (ROS) as by-products of the metabolic breakdown of sugars, fats and proteins. Anabolic pathways then build macromolecules out of the products of catabolism, which are building blocks for cell structures and help to maintain the cell. Catabolic pathways-for example glycolysis, oxidative phosphorylation via tricarboxylic acid cycle (TCA) and lipogenesis-involve the breakdown of major nutrients (glucose, amino acids and fatty acids) to generate energy, which is either stored for later use or released as heat.
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