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Genetic alterations and epigenetic modifications of cancer cells result in cellular metabolic pathways that are different in comparison to normal cells. Due to the inherent genetic instability of cancer cells, tumors are heterogeneous with a myriad microenvironments and multiple altered metabolic pathways, which could provide useful cancer therapeutic targets.
Figure 1: In cancer cells, increased transporter expression facilitates increased uptake of substrates for metabolic pathways including glycolysis, pentose phosphate pathway (PPP), oxidative phosphorylation (OXPHOS) and lipidogenesis. Mutant enzymes and abnormal regulation of these key pathways, drive cellular proliferation and promote cell survival. Furthermore, alterations in pH and the redox balance provide cytoprotective advantages and promote invasion and cell survival (broken arrow = additional intermediate steps not shown).
Taken from the Cancer Research Product Guide Edition 3, 2015. Request or download your copy today!
In 1924 Otto Warburg first discovered that cancer cells generated a large proportion of their ATP by metabolizing glucose via aerobic glycolysis (as opposed to mostly through oxidative phosphorylation (OXPHOS) in normal cells). Initially it was thought that this Warburg effect was a cause of cancer, but it was later established that this shift to glycolytic metabolism was an effect of cancer cell transformation. Malignant transformation and altered metabolism go hand in hand, because the rapid increase in proliferation places increased demand on metabolic processes that cannot be met by conventional cellular metabolism. Metabolic rearrangement has been associated with inactivation of tumor suppressor genes and the activation of oncogenes, as well as with abnormal mutant enzyme (oncoenzyme) activity and the accumulation of tumorigenic metabolites (oncometabolites).
Cancer cells require three crucial metabolic adaptations in order to rapidly proliferate and survive: an increase in ATP production to fuel their high energy needs; an increased biosynthesis of the three major classes of cellular building blocks: proteins, lipids and nucleic acids; and an adapted redox system to counteract the increase in oxidative stress.
Figure 1: Genetic and epigenetic mutations in cancer cells can alter the regulation of metabolic pathways. This results in increased biosynthesis, abnormal bioenergy production and an altered redox balance, all of which promotes cell proliferation and survival. Furthermore, microenvironments within large tumors can dynamically alter metabolic pathways creating heterogeneous populations of cells.
Taken from Cancer Metabolism, Cancer Research Product Guide Edition 3, 2015.
Malignant transformation is associated with the following: a shift from OXPHOS to glycolysis as the main source of ATP; an increase in glucose metabolism through the pentose phosphate pathway (PPP); an increase in lipid biosynthesis; high glutamine consumption, and alterations in pH and redox regulation to accommodate this need. Furthermore, the enhanced rate of glycolysis produces large quantities of lactate which needs removing from the cell, so increased expression of lactate transporters is also often observed in cancer cells.
Another commonly seen adaptation is an increase in the number of glutamine transporters. These are required to facilitate the increased demand for glutamine (termed glutamine addiction) in lipid biosynthesis and NADPH production. In addition there is an increase in uptake of glycine and serine for amino acid biosynthesis and the replenishment of Krebs cycle intermediates. These altered pathways allow for the sufficient supply of nucleic acids, proteins and membrane lipids required to sustain the increased demands of highly proliferative cells.
Glucose and glutamine can be broken down into the precursors of many cellular building blocks, as well as facilitating ATP production. Increased glucose and glutamine catabolism also leads to abundant NADPH production, which has cytoprotective effects and allows the cancer cell to buffer extra oxidative damage sustained through rapid proliferation. The glucose transporter (GLUT) family of transporters and amino acid transporter 2 (ASCT2) are responsible for the increased uptake of glucose and glutamine respectively, thus making them promising targets for anticancer drugs.
As the Warburg effect describes, cancer cells display significantly enhanced rates of glycolysis. Therefore small molecules that target glycolytic enzymes and transporters are being investigated as selective anticancer therapies. These targets include hexokinase, 6-phosphofructo-2-kinase/fructose- 2,6-bisphosphatase (PFKFB3), monocarboxylate transporter (MCT) and lactate dehydrogenase A (LDHA). Several in vitro and in vivo models of cancer have shown that small molecule inhibitors of these targets can limit the growth and survival of certain types of tumor.
Glucose is broken down into pyruvate, which is then transported into the mitochondria. It is converted into acetyl-CoA before entering the Krebs cycle, producing energy in the form of ATP, precursors for amino acid synthesis and the reducing agent NADH.
One of the major enzymes that feeds into the cycle is glutamate dehydrogenase (GDH), which converts glutamate to α-ketoglutarate (α-KG), an essential intermediate in the Krebs cycle. Inhibition of GDH has been shown to suppress the use of glutamine in the Krebs cycle and sensitizes glioblastoma cells to glucose withdrawal. α-KG is a substrate for the mutant form of isocitrate dehydrogenase (mIDH), which has been linked to oncogenesis. mIDH converts α-KG to D-2-hydroxyglutarate (D2HG) resulting in high intracellular levels of D2HG. D2HG competitively blocks α-KG binding at a family of enzymes called 2-OG-dependent dioxygenases, which are regulators of important epigenetic events. IDH enzyme mutants are strongly associated with hypermethylation of CpG islands in acute myeloid leukemia (AML) and glioblastomas.
Recent evidence suggests that in certain types of cancer, such as prostate cancer, the initiation of cancer cell proliferation relies more on lipid metabolism than glycolysis. Targeting fatty acid synthesis can cripple a cell's ability to proliferate and survive because it limits lipid membrane production, which is essential for cellular expansion, as well as blocking β-oxidation of fatty acids in mitochondria.
Cancer cells are able to survive in their hostile microenvironments because of increased expression of proton pumps and ion transporters. Aberrant regulation of hydrogen ions leads to a reversal of the pH gradient across tumor cell membranes, resulting in an increased basic intracellular pH (pHi) and a more acidic extracellular pH (pHe). It is critical to cancer cell survival that the intracellular environment does not become acidified because this could induce apoptosis. Under hypoxic conditions HIF-1 induces carbonic anhydrase IX (CA IX) expression, which regulates cellular pH. Protons generated by CA IX activity decrease pHe, potentiating extracellular matrix destruction and tumor cell invasiveness.
Redox dysfunction is common in cancer cells owing to their altered metabolism. This results in an excess production of ROS, which damage free nucleoside triphosphates (dNTPs). During DNA replication, these dNTPs become incorporated into DNA, resulting in mutagenesis and cell death. MutT homolog-1 (MTH1) is an enzyme that hydrolyzes oxidized dNTPs, preventing them from becoming incorporated into DNA. Cancer cells, unlike normal cells, are proposed to depend on MTH1 activity for survival, making it an attractive therapeutic target because it is cancer phenotypically lethal.
Antimetabolites have long been used clinically as standard components of chemotherapy. However, the similarities between metabolic pathways in malignant cells and healthy cells that have high proliferation rates result in a small therapeutic window. Therefore, identifying therapeutic targets that selectively kill tumor cells is a major challenge of cancer metabolism research.
Through exploiting therapeutic windows for antimetabolites, targeting unique mutant enzymes and aberrant metabolic pathways, it is hoped that new tools will be found to add to the arsenal of cancer treatments.
For a more thorough introduction to cancer metabolism, please download or request the Tocris Cancer Research Product Guide.
Tocris offers the following scientific literature for Cancer Metabolism to showcase our products. We invite you to request* or download your copy today!
*Please note that Tocris will only send literature to established scientific business / institute addresses.
This poster summarizes the main metabolic pathways in cancer cells and highlights potential targets for cancer therapeutics. Genetic changes and epigenetic modifications in cancer cells alter the regulation of cellular metabolic pathways providing potential cancer therapeutic targets.