Warburg effect and its advantage in cancer cells
Cancer cells rewire their metabolism to promote growth, survival, proliferation, and long-term maintenance. The common feature of this altered metabolism is the increased glucose uptake and fermentation of glucose to lactate. This phenomenon is observed even in the presence of completely functioning mitochondria and, together, is known as the ‘Warburg Effect’.
The Warburg Effect has been proposed to be an adaptation mechanism to support the biosynthetic requirements of uncontrolled proliferation (Figure 2). In this scenario, the increased glucose consumption is used as a carbon source for anabolic processes needed to support cell proliferation. This excess carbon is diverted into the multiple branching pathways that emanate from glycolysis, and is used for the generation of nucleotides, lipids, and proteins. One example is the diversion of glycolytic flux into de novo serine biosynthesis through the enzyme phosphoglycerate dehydrogenase (PHGDH) . In addition to the usage of additional carbon from enhanced glucose metabolism for cellular building blocks, a now famous argument is that, rather than having a rate-limiting demand for ATP, proliferating cells are in greater need of reducing equivalents in the form of NADPH. Increased glucose uptake allows for greater synthesis of these reducing equivalents in the oxidative branch of the pentose phosphate pathway, which are then used in reductive biosynthesis, most notably in de novo lipid synthesis.
Another proposed mechanism to account for the biosynthetic function of the Warburg Effect is the regeneration of NAD+ from NADH in the pyruvate to lactate step that completes aerobic glycolysis. In this scenario, NADH that is produced by glyceraldehyde phosphate dehydrogenase (GAPDH) must be consumed to regenerate NAD+ to keep glycolysis active. This high rate of glycolysis allows for supply lines to remain open that can, for example, siphon 3-phosphoglycerate (3PG) to serine for one-carbon metabolism-mediated production of NADPH and nucleotides [17,25]. These proposals together conclude that the Warburg Effect supports a metabolic environment that allows for rapid biosynthesis to support growth and proliferation. Furthermore, others have proposed that aerobic glycolysis is a tradeoff to support biosynthesis. In these scenarios, the inefficient way of making ATP occurs as a cost of maintaining high fluxes through anabolic pathways. These pathways require increased expression of biosynthesis genes, such as those involved in nucleotide and lipid metabolism, and the tradeoff occurs by limiting the use of mitochondria to preserve the high expression of biosynthetic enzymes in the face of the limited number of proteins that can be made. Another scenario of such a trade off comes from the idea that the physical volume available per cell may limit mitochondria number and, thus, any requirements for energy and biomass that exceed the limited mitochondrial capacity needs to be produced from aerobic glycolysis. This concept has been termed the ‘solvent capacity constraint’. In both these cases, the Warburg Effect is an adaptation to support biomass production in the face of limited options for ATP generation. The attractiveness of this proposal comes in part from its ability to provide a simple explanation for the apparent correlation between aerobic glycolysis and cell growth and proliferation.
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Journal of Molecular Oncology Research