Cancer Metabolism

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.

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Literature

Cancer Metabolism Therapeutic Targets

Taken from Cancer Metabolism, Cancer Research Product Guide Edition 3, 2015

Cancer Metabolism

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).

Metabolic Alterations in Cancer Cells

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.


Abnormal Cancer Metabolism

Taken from Cancer Metabolism, Cancer Research Product Guide Edition 3, 2015

Cancer Metabolism

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 Transporters

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.

Glycolysis and the Pentose Phosphate Pathway

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.

Krebs Cycle

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.

Lipidogenesis

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 pr

Literature for Cancer Metabolism

Cancer

Cancer Research Product Guide

A collection of over 750 products for cancer research, the guide includes research tools for the study of:

  • Cancer Metabolism
  • Epigenetics in Cancer
  • Receptor Signaling
  • Cell Cycle and DNA Damage Repair
  • Angiogenesis
  • Invasion and Metastasis
Cancer Metabolism

Cancer Metabolism Poster

Adapted from the 2015 Cancer Product Guide, Edition 3, this poster summarizes the main targets for cancer metabolism researchers. Genetic changes and epigenetic modifications in cancer cells alter the regulation of cellular metabolic pathways. These distinct metabolic circuits could provide viable cancer therapeutic targets.