Cancer

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.

Cellular Metabolism and Anticancer Effects

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.

    • Glucose Metabolism Inhibition and Anticancer Effects
      • Glucose Metabolism Inhibition and Anticancer Effects

        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


        Products

        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

    • Amino Acid Metabolism Inhibition and Anticancer Effects
      • Amino Acid Metabolism Inhibition and Anticancer Effects

        In cancer cells, which are actively proliferating, amino acids are essential for the synthesis of proteins and nucleic acids. Furthermore, many cancer cells downregulate acetyl CoA production from pyruvate, requiring cancer cells to also use amino acids as nutrient sources for the TCA cycle. This explains why cancer cells have been shown to increase expression of amino acid transporters to take up large amounts of amino acids.

        Glutamine is a raw material for glutathione and a source of α-ketoglutarate, which is essential for the TCA cycle. For these reasons, glutamine uptake and glutaminolysis (glutamine metabolism) have attracted attention as drug targets. As well, the amino acid transporter LAT (L-type amino acid transporter), which is involved in the uptake of many essential amino acids, was found to be overexpressed in many cancer cells. LAT is expected to a be future drug target.

        Because cancer cells produce a large amount of reactive oxygen species, they maintain redox balance by increasing the production of glutathione, an antioxidant. Thus, inhibition of the pathways involved in glutathione production can change the intracellular redox balance and induce methods of cell death such as ferroptosis. In addition to the reason just stated, glutathione also contributes to drug resistance, which is why the pathway involved in glutathione production has become a major target for drug development.

        Cysteine is an amino acid also required for redox regulation and is mainly taken up into cells by the cystine transporter (xCT). Sulfasalazine, long used as an anti-inflammatory drug, and sorafenib, a molecular targeted therapy for cancer, have recently been shown to inhibit xCT. For the same cell death-mediated anticancer effect as glutathione inhibition, xCT has also attracted attention as a target for drug development.

        Changes in Intracellular Metabolism by Each Inhibitor / References

        Cell Line Inhibitor / Inducer Changes to Cellular Metablism Publication
        KO99L LAT1 inhibitor: JPH203 Mitochondrial MP↓ Leukemia, 2015, 29, 1253
        Autophagy↑
        LS174T LAT1 inhibitor: JPH203 Glutamine uptake↓ J. Biol. Chem., 2018, 293 (8), 2877
        A549 Leucine uptake↓
        HeLa LAT1 inhibitor: BCH Tryptophan uptake↓ J. Immunol., 2011, 187 (4), 1617
        A549 ASCT2 inhibitor: GPNA Glutamine uptake↓ Clin. Cancer Res., 2013, 19 (3), 560
        ROS↑
        MG63.3 GLS inhibitor: CB839 Glutamine↑ Cancer&Metab., 2020, 8:4
        Glutamate↓, GSH↓
        OCI-AML3 GLS inhibitor: CB839 ATP↓, NADH/NAD↓ Mol. Cancer Ther., 2019, 18 (11), 1937
        GSH/GSSG↓, Alanine↓
        Glutamate↓
        H1299 GDH inhibitor: R162 ROS↑ Cancer Cell, 2015, 27, 257
        MDA-MB231 GPx activity↓
        A2780 xCT inhibitor: Erastin Cystine uptake↓ Sci. Rep., 2018, 8 (1), 968
        GSH↓
        B16-F10 xCT inhibitor: Sulfasalazine GSH↓ PLoS One., 2018, 13 (4), e0195151.
        ROS↑
        HT-1080 xCT inhibitor: Sorafenib Cystine uptake↓, GSH↓ Elife, 2014, 3, e02523
        Lipid peroxidation↑
        PANC-1 GCL inhibitor: BSO GSH↓ Oncol. Lett., 2018, 15 (6), 8735
        Lipid peroxidation↑
        A549 GCL inhibitor: BSO Cystine uptake↓, GSH↓ Toxicol. Appl. Pharmacol., 1985, 381

        Products

        Objective Product Name CAT. No.
        NAD+/NADH Assay NAD/NADH Assay Kit-WST N509
        JC-1 Mitochondrial Membrane Potential Detection JC-1 MitoMP Detection Kit MT09
        MT-1 Mitochondrial Membrane Potential Detection MT-1 MitoMP Detection Kit MT13
        Total ROS Detection ROS Assay Kit-Highly Sensitive DCFH-DA- R252
        Glutamine Assay Glutamine Assay Kit-WST G268
        Glutamate Assay Glutamate Assay Kit-WST G269
        Glutathione Quantification GSSG/GSH Quantification Kit G257
        Lipid Peroxide Detection Liperfluo L248
        Mitochondrial Lipid Peroxide Detection MitoPeDPP M466
        Autophagosome Detection DAPGreen - Autophagy Detection D676
        DAPRed - Autophagy Detection D677

    • Fatty Acid Metabolism Inhibition and Anticancer Effects
      • Cancer cells, which are actively proliferating, naturally require a large amount of lipids. Thus, intracellular fatty acid synthesis and extracellular fatty acid uptake are both very active. Therefore, many cancer cells have enhanced lipid droplet accumulation. Consequently, the pathway involved in fatty acid production is a very popular therapeutic target for cancer, and many inhibitors have been developed. Additionally, cancer cells perform β-oxidation of fatty acids for efficient energy production in order to compensate for inefficient energy production by the glycolytic system. Thus, drugs targeting the β-oxidation of fatty acids are also being developed.

        Fatty Acid Metabolism Inhibition and Anticancer Effects

        Changes in Intracellular Metabolism by Each Inhibitor / References

        Cell Line Inhibitor / Inducer Changes to Cellular Metabolism Publication
        CD36 Highly expressed MCF7, SUM159 CD36 inhibitor: SSO Fatty acid uptake↓
        Lipid droplet↓
        Cancers, 2019, 11, 2012
        A375, SKMel28 FATP inhibitor: Lipofermata Fatty acid uptake↓
        Lipid droplet↓
        Cancer Discov., 2018, 8 (8), 1006
        BT474, MCF7, T47D ACACA inhibitor: TOFA Lipid droplet↓
        FA oxidation↓
        J. Clin. Med., 2020, 9, 87

        ccRCC

        SREBP inhibitor: Betulin
        ACACA inhibitor: TOFA
        FASN inhibitor: C75
        Lipid droplet↓ Mol. Cell Biol., 2017, 37 (22), e00265-17
        NCI-H1703 ACSL inhibitor: Triacsin C Lipid droplet↓ Int. J. Cancer, 2020, 147, 1680
        UM-UC-3 FAO inhibitor: Etomoxir Lipid droplet↑
        ATP↓, NADPH↓
        Clin. Sci., 2019, 133 (15), 1745

        SF188

        FAO inhibitor: Etomoxir ATP↓, NADPH↓
        GSH↓
        ROS↑
        Biochim. Biophys. Acta, 2011, 1807 (6), 726

        Products

        Objective Product Name CAT. No.
        Lipid Droplet Assay Lipid Droplet Assay Kit-Blue LD05
        Lipid Droplet Assay Kit-Deep Red LD06
        Lipid Droplet Staining Lipi-Blue LD01
        Lipi-Green LD02
        Lipi-Red LD03
        Lipi-Deep Red LD04
        NADP+/NADPH Assay NADP/NADPH Assay Kit-WST N510
        Glutathione Quantification GSSG/GSH Quantification Kit G257
        Total ROS Detection ROS Assay Kit -Highly Sensitive DCFH-DA- R252

    • Cancer Immunity and Cellular Metabolism
      • T cells play a central role in the immune system by eliminating cancer cells. In recent years, it has become clear that metabolism is also involved in the regulation of T cell functions such as differentiation and activation, inspiring more active research on metabolism in cancer immunity.

        Cancer cells take in large amounts of nutrients to maintain their proliferative activity. Activated T cells also require large amounts of nutrients to eliminate cancer cells. Cancer cells and activated T cells thus compete for nutrients - particularly glucose.

        Activated T cells express the PD-1 immune checkpoint receptor on their surface. Cancer cells, in turn, express PD-L1, as the interaction will suppress T cell glucose uptake. It is in this way that cancer cells will regulate the metabolism of immune cells in order to evade the immune system. Therefore, it is important to understand the metabolism of not only cancer cells but also immune cells for the sake of cancer immunology.

        Cancer Immunity and Cellular Metabolism

        Changes in Intracellular Metabolism by Each Inhibitor / References

        Cell Line Antigen Activation Changes to Cellular Metabolism Publication
        T cell Activation Glucose uptake ↑ J. Immunol., 2008, 180, 4476
        CD8 (+) T cell Activation Glucose uptake ↑
        FAO ↓
        J. Clin. Invest., 2013, 123, 4479
        CD4 (+) T cell Activation Glucose uptake ↑
        Lactate ↑, ATP ↑
        eLife, 2018, 7, e30938
        CD4 (+) T cell Activation Glucose uptake ↑, Lactate ↑
        Glutamine uptake ↑
        FAO ↓
        Nat. Commun., 2015, 6, 6692
        CD4 (+) T cell Activation
        (Interactions between PD-1 & PDL1)
        Glucose uptake ↓, Lactate ↓
        Glutamine uptake ↓
        FAO ↑

        Products

        Objective Product Name CAT. No.
        Glucose Metabolism Assay Glucose Assay Kit-WST G264
        Glucose Uptake Assay Glucose Uptake Assay Kit-Green UP02
        Lactate Detection Lactate Assay Kit-WST L256
        Glutamine Detection Glutamine Assay Kit-WST G268
        Glutamate Detection Glutamate Assay Kit-WST G269
        ATP Measurement ATP Assay Kit-Luminescence A550

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