Metabolism within the cell - a powerful tool in understanding disease

Description

Analysis of intracellular metabolic systems, such as glycolysis, TCA cycle, and the electron transport chain, is important for understanding the condition of the cell. The condition of these intracellular metabolic systems can be evaluated by measuring metabolites like glucose, lactate, NAD(P)/NAD(P)H, glutamine, and glutamate as indicators of their activity.

Diseases and associated metabolic changes

Measurement of intracellular metabolism in disease models such as cancer and diabetes has been attracting attention in recent years. Here are some examples of cellular metabolism measurements in the following diseases.

 

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Cancer

Cancer cells rapidly take in and metabolize large amounts of nutrients in order to produce proteins, nucleic acids, and energy-rich compounds such as ATP, which are necessary to maintain cell growth. In addition, cancer cells can survive under adverse conditions, such as hypoxia and low nutrition, by altering their metabolic system.Therefore, research on cancer cell metabolism has been actively pursued in recent years.

 

Cancer cells use the less-efficient glycolytic system to produce ATP, rather than mitochondrial oxidative phosphorylation, in a phenomenon known as the Warburg effect. Therefore, cancer cells ingest large amounts of sugar, increasing the production of lactate via the glycolytic system. Furthermore, mitochondria in cancer cells use amino acids and lipids to generate NADH, and it is thought that NADH in mitochondria is mainly used for redox regulation in addition to ATP generation. The mitochondria of cancer cells have different characteristics from those of normal cells, resulting in an increase in mitochondrial membrane potential (hyperpolarization) and overproduction of reactive oxygen species (ROS) in cancer cells. Cancer cells produce glutathione (GSH), which scavenges ROS to maintain the intracellular redox balance. As a result, cancer cells take in more glutamine and cysteine, which are essential for glutathione production, than normal cells. Additionally, NADPH is required to maintain GSH levels. Cancer cells maintain high NADPH levels via production of NADPH in the mitochondrial and pentose phosphate pathways.
Note: Although this information is generally true of cancer cell metabolism, specific metabolism characteristics may vary, depending on cancer cell type, environment, and culture conditions.

 

References

See also the following reviews on cancer metabolism research.

1) Glycolysis: M. G. Vander Heiden, L. C. Cantley, and C. B. Thompson, “Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation”, Science, 2009324, 1029.
2) Amino acid metabolism, ROS : P. Koppula, Y. Zhang, and B. Gan, “Amino Acid Transporter SLC7A11/xCT at the Crossroads of Regulating Redox Homeostasis and Nutrient Dependency of Cancer”, Cancer Commun., 201838, 12.
3) Amino acid metabolism:  E. L. Lieu, T. Nguyen, S. Rhyne, and J. Kim, “Amino Acids in Cancer”, Exp. Mol. Med.202052, 15
4) Mitochondria、ROS、NADPH: F. Ciccarese and V. Ciminale, “Escaping Death: Mitochondrial Redox Homeostasis in Cancer Cells”,  Front. Oncol. 2017 7, 117.
5) NADH: A. Chiarugi, C. Dolle, R. Felici, and M. Ziegler, “The NAD Metabolome-A Key Determinant of Cancer Cell Biology”, Nat. Rev. Cancer, 201212, 741.

 

Inhibition of glucose metabolism and anticancer effects

Since cancer cells mainly use glycolysis to produce ATP, many anticancer drugs have been developed to target glycolysis. Although effective anticancer drugs have not yet been developed for it, glycolysis remains a major target for anticancer drug development. Since cancer cells take up a large amount of sugar via glucose transporters, direct inhibition of glucose transporters can suppress glycolysis. Therefore, glucose transporters (GLUTs) have become target proteins in the development of anticancer drugs. Inhibition of glycolytic enzymes (hexokinase : HK, lactate dehydrogenase: LDH, etc.), glucose starvation, and inhibition of extracellular efflux of lactate, the end product of glycolysis, are also effective strategies for the development of anticancer drugs.

Reference (Changes in intracellular metabolism induced by each inhibitor)

Cell Drugs or stimulation State of intracellular metabolism Reference

Ovarian Cancer(SKOV3、OVCAR3、HEY、A2780)

GLUT1 inhibitor:BAY-876

ATP↓、​Lactate↓

Cancer, 201911, 33

Lung Cancer(H1299、H460、H2030)

GLUT1 suppression of expression:Apigenin

Glucose consumption↓

Lactate↓、ATP↓

NADPH↓、GSH/GSSG↓

ROS↓

Int. J. Oncol.201648, 399

Colorectal Cancer (HCT116)

HK inhibitor:2-DG

Glucose uptake ↓

Lactate↓、Acetyl-CoA↓

H3K27Ac↓

Cancer Metab., 2015, 3, 10

Ovarian Cancer(SKOV3、HEY)

HK inhibitor:2-DG + Metformin

ATP↓、Lactate↓

Am. J. Transl. Res.20168, 4821

Colon Cancer(CT26)

Complex I inhibitor:Phenformin、

LDH inhibitor:Oxamate

Glucose uptake↓

Lactate↓、ATP↓

ROS↑

PLoS One.20149, e85576

Human Lymphoma(P493)

LDH inhibitor:FX11

ATP↓、Lactate↓

NADH/NAD↑、ROS↑

Mitochondrial membrane potential↓

Proc. Natl. Acad. Sci. USA, 2010107(5), 2037

Human Lymphoma (Raji)

MCT inhibitor:AZD3965

Glucose uptake↓

Intracellular Lactate↑

(Extracellular Lactate↓)

Cancer Res.201777(21), 5913

 

Related products

Application Product name Code
Glucose Metabolism Measurement Kit Glucose Assay Kit-WST G264
Lactate Measurement Kit Lactate Assay Kit-WST L256
NAD/NADH Measurement Kit NAD/NADH Assay Kit-WST N509
NADP/NADPH Measurement Kit NADP/NADPH Assay Kit-WST N510
JC-1 Mitochondrial membrane potential detection kit JC-1 MitoMP Detection Kit MT09
MT-1 Mitochondrial membrane potential detection kit MT-1 MitoMP Detection Kit MT13

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