Cancer cells rapidly take in large amounts of nutrients in order to maintain active cell growth. They metabolize these nutrients to synthesize and nucleic acids and to produce energy such as ATP. Even under unfavorable conditions, such as hypoxia or low nutrition, cancer cells can survive by altering their metabolic systems. Therefore, the metabolic systems of cancer cells have attracted many researchers' attention.
A recurring characteristic of cancer cell metabolism is that cancer cells generally prefer to produce ATP via the glycolytic system despite that system being less efficient than mitochondrial oxidative phosphorylation (Warburg effect). As a result, cancer cells take up large amounts of glucose. They also produce a large amount of lactate due to increased glycolytic activity. This method of ATP production allows cancer cells to proliferate even under hypoxia, because the glycolytic system does not require oxygen. Meanwhile, the mitochondria of cancer cells use amino acids and fats to produce NADH. It is commonly recognized that NADH in cancer cell mitochondria is mainly used for redox regulation in addition to ATP production. The abnormal functions of mitochondria in cancer cells result in increased mitochondrial membrane potential (hyperpolarization) and excessive ROS production. Consequently, they produce large amounts of glutathione to maintain the redox balance. Since glutamine and cysteine are essential nutrients for glutathione production, cancer cells take up large amounts of these amino acids. Additionally, since NADPH is required to maintain the reduction of glutathione, the pentose phosphate pathway (downstream from the glycolytic system) and NADH in mitochondria are used to maintain high NADPH levels.
Note: the above information represents the general metabolic characteristics of cancer cells and may vary depending on the type of cancer cell and its environment.
Cancer cells mainly use the glycolytic system to produce ATP. Thus, the glycolytic system is the most important pathway to understand in the metabolism of cancer cells. Consequently, the glycolytic system has long been a target of anticancer drug development. Although effective anticancer drugs have not yet been developed, the glycolytic system remains a major drug target.
One of the drug discovery target proteins of the glycolytic system is the glucose transporter (GLUT). Since cancer cells take up large amounts of sugar via glucose transporters, it is possible to suppress the glycolytic system by directly inhibiting glucose transporters. Inhibition of the enzymes responsible for glucose starvation and glycolysis [hexokinase (HK), lactate dehydrogenase (LDH), etc.] as well as inhibition of the efflux of lactate (the end product of glycolysis) are also effective.
Cell Line | Inhibitor / Inducer | Changes to Cellular Metabolism | Publication |
---|---|---|---|
KO99L | LAT1 inhibitor: JPH203 | Mitochondrial MP↓ Autophagy↑ |
Leukemia, 2015, 29, 1253 |
LS174T A549 |
LAT1 inhibitor: JPH203 | Glutamine uptake↓ Leucine uptake↓ |
J. Biol. Chem., 2018, 293 (8), 2877 |
HeLa | LAT1 inhibitor: BCH | Tryptophan uptake↓ | J. Immunol., 2011, 187 (4), 1617 |
A549 | ASCT2 inhibitor: GPNA | Glutamine uptake↓ ROS↑ |
Clin. Cancer Res., 2013, 19 (3), 560 |
MG63.3 | GLS inhibitor: CB839 | Glutamine↑ Glutamate↓, GSH↓ |
Cancer&Metab., 2020, 8:4 |
OCI-AML3 | GLS inhibitor: CB839 | ATP↓, NADH/NAD↓ GSH/GSSG↓, Alanine↓ Glutamate↓ |
Mol. Cancer Ther., 2019, 18 (11), 1937 |
H1299 MDA-MB231 |
GDH inhibitor: R162 | ROS↑ GPx activity↓ |
Cancer Cell, 2015, 27, 257 |
A2780 | xCT inhibitor: Erastin | Cystine uptake↓ GSH↓ |
Sci. Rep., 2018, 8 (1), 968 |
B16-F10 | xCT inhibitor: Sulfasalazine | GSH↓ ROS↑ |
PLoS One., 2018, 13 (4), e0195151. |
HT-1080 | xCT inhibitor: Sorafenib | Cystine uptake↓, GSH↓ Lipid peroxidation↑ |
Elife, 2014, 3, e02523 |
PANC-1 | GCL inhibitor: BSO | GSH↓ Lipid peroxidation↑ |
Oncol. Lett., 2018, 15 (6), 8735 |
A549 | GCL inhibitor: BSO | Cystine uptake↓, GSH↓ | Toxicol. Appl. Pharmacol., 1985, 381 |
Objective | Product Name | CAT. No. |
---|---|---|
Glucose Metabolism Assay | Glucose Assay Kit-WST | G264 |
Glucose Uptake Assay | Glucose Uptake Assay Kit-Green | UP02 |
Lactic Acid Measurement | Lactate Assay Kit-WST | L256 |
NAD+/NADH Assay | NAD/NADH Assay Kit-WST | N509 |
NADP+/NADPH Assay | NADP/NADPH Assay Kit-WST | N510 |
JC-1 Mitochondrial Membrane Potential Detection | JC-1 MitoMP Detection Kit | MT09 |
MT-1 Mitochondrial Membrane Potential Detection | MT-1 MitoMP Detection Kit | MT13 |
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