Otto Warburg was the first to discover in 1924 that cancer cells generated a large proportion of their adenosine triphosphate (ATP) by metabolizing glucose via aerobic glycolysis. This was in sharp contrast to ATP production through oxidative phosphorylation (OXPHOS) in normal cells.
Initially, it was believed that this Warburg effect caused cancer, but it was later discovered that this shift to glycolytic metabolism was an effect of the transformation of cancer cells. The regulation of cellular metabolic pathways in cancer cells can be altered by genetic changes and epigenetic modifications. These distinct metabolic circuits could provide viable targets in cancer therapy.
Abnormal Cancer Metabolism
Fig 1. A flow chart showing the causes and effects of Abnormal Cancer Metabolism.
Main Targets in Cancer Metabolism
Glycolysis, Pentose Phosphate Pathway, and Transporters
Enhanced rates of glycolysis (approximately 200-fold) are known to produce increased levels of ATP in a far more rapid manner than OXPHOS. However, this process is far less efficient, resulting in an increased demand for glucose. As such, glucose transporter (GLUT) expression is frequently increased in cancer cells, along with monocarboxylate transporter (MCT) expression. Both remove the increasing levels of lactate from the cells.
Another adaptation that is commonly seen is an increased number of glutamine transporters. The first step in glutamine catabolism involves the hydrolysis of glutamine into glutamate and ammonia by glutaminase (GLS1), which is vital in lipid biosynthesis and NADPH production.
Further, this also causes an increase in the flux through the pentose phosphate pathway (PPP). The PPP is required for the generation of precursors for amino acid synthesis and NADPH (an integral component in lipid and nucleotide synthesis, as well as redox homeostasis). Glucose is directed into either the PPP or glycolysis pathway (or both), depending on the requirements of the cancer cell.
For instance, during high oxidative stress, cancer cells divert the flux of glucose away from glycolysis into the PPP to produce more NADPH.
Glucose breaks down into pyruvate, which then gets transported into the mitochondria, where it is converted into acetyl-CoA. This then enters the Krebs cycle. The process produces energy in the form of ATP, as well as precursors for amino acid synthesis and the reducing agent NADPH.
Glutamate dehydrogenase (GDH) is one of the major enzymes that feeds into the Krebs cycle, converting glutamate to α-ketoglutarate (α-KG). α-KG is an essential component in the Krebs cycle. Inhibition of GDH is known to suppress the use of glutamine in the Krebs cycle and sensitize glioblastoma cells to glucose withdrawal.
Mutant forms of isocitrate dehydrogenase (IDH), which have been linked to oncogenesis, use α-KG as a substrate. Mutant IDH converts α-KG to D-2-hydroxyglutarate (D2HG), which results in high intracellular levels of D2HG. Further, D2HG competitively blocks α-KG binding at a family of enzymes called 2-OG-dependent dioxygenases, which function as regulators of important epigenetic events. What’s more, IDH mutations impair cell redox capacity.
Recent evidence has shown that the initiation of cell proliferation relies more on lipid metabolism than glycolysis, in certain types of cancer such as prostate cancer. In fact, the targeting of fatty acid synthesis can hamper a cell’s ability to proliferate and survive because it limits lipid membrane production. It also blocks β-oxidation of fatty acids in mitochondria.
pH and Redox Balance
Cancer cells can survive in their hostile microenvironments due to the increased expression of proton pumps and ion transporters. However, aberrant regulation of the hydrogen ions can cause a reversal of the pH gradient across tumor cell membranes.
This then results in a more basic intracellular pH (pHi) and a more acidic extracellular pH (pHe). It is critical to the survival of cancer cells that the intracellular environment does not become acidified since such a scenario could induce apoptosis.
Altered Regulation of Metabolic Pathways - Abnormal Cancer Metabolism in Cancer Cells
Fig 2. A diagram showing the altered regulation of metabolic pathways when abnormal cancer metabolism in cancer cells occurs.
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