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Targeted Therapy for Cancer Stem Cells
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Rama Krishna Nimmakayala, Saswati Karmakar, Garima Kaushik, Sanchita Rauth, Srikanth Barkeer, Saravanakumar Marimuthu, Moorthy P. Ponnusamy
We now know that glycolysis and oxidative phosphorylation are not the only metabolic pathways utilized by CSCs for their energy requirements. Amino acid metabolism, especially glutaminolysis and fatty acid metabolism, also play an essential role in cancer development and growth. Currently, there is a lack of knowledge on the compensatory effect between metabolic pathways, the effect of blocking one part of the pathway on the overall signaling, and most importantly, the metabolic phenotype of patients. Therefore, a comprehensive analysis of the metabolic landscape of CSCs from early to late stages of PC progression is needed. Given that only a few permitted metabolic types will be compatible with the functional properties of CSCs, metabostemness trait is very relevant for tackling the problem of tumor heterogeneity and, ultimately, is capable of discovering drugs aimed at targeting CSCs themselves.
The Physiology of Digestion, Absorption, and Metabolism in the Human Intestine
Published in Victor R. Preedy, Ronald R. Watson, Alcohol and the Gastrointestinal Tract, 2017
Windmueller observed that luminal asparagine was quantitatively transferred to the portal circulation whereas luminal glutamine was extensively metabolized as was luminal glutamate.209 This has been confirmed in organ balance studies in dogs212,213 which showed that in the fasting state, intestinal glutamine consumption was 1.4 ± 0.2 μmol/kg/min compared to glucose consumption of 4.1 ± 1.2 μmol/kg/min. Glutamine consumption was further increased to 4.6 ± 0.7 μmol/kg/min by glutamine infusion, whereas glucose infusion elicited no marked increase in intestinal glucose oxidation.212,213 These data clearly suggested that glutamine plays a major part in the metabolism of the intestine. An early suggestion by McKeehan was that high glutamine consumption ("glutaminolysis") was the hallmark of any cell type with high rates of proliferation.214 His analysis showed that this was not for reasons of energy metabolism, since glycolysis could also meet the energy needs of these cells. Newsholme has provided an elegant metabolic dissection of the relative metabolic requirements of cells with rapid turnover (e.g., mucosal cells), with potential for rapid turnover (e.g., resting lymphocytes) or with high metabolic requirements but no need for rapid turnover (e.g., muscle, macrophages). Where high rates of glutamine consumption existed, it appeared not to be for energy production entirely.215,216 Instead, Newsholme has proposed that high consumption provides control for other metabolic pathways which branch from the main pathway. Thus, glucose and glutamine metabolism also provide precursors for ribose (RNA, DNA) synthesis and for purine and pyrimidine (RNA, DNA) synthesis. If this is correct, then the role of glutamine is in maintenance of cell turnover rather than of energy production. Thus, it has a theoretical role in maintaining the mucosal barrier function of the gut, and of associated immune cells.
Characteristics, Events, and Stages in Tumorigenesis
Published in Franklyn De Silva, Jane Alcorn, The Elusive Road Towards Effective Cancer Prevention and Treatment, 2023
Franklyn De Silva, Jane Alcorn
Dysregulation of cellular metabolism involves three major metabolic pathways: (i) aerobic glycolysis, (ii) glutaminolysis, and (iii) one-carbon metabolism [1027]. These metabolic pathways allow malignant cells to shift from making ATP to producing considerable quantities of amino acids, nucleotides, fatty acids, and other intermediates needed for energy and survival [1027]. Although Otto Warburg had initially identified cancer as having a distinct metabolic phenotype (i.e., the Warburg effect) in the 1920s, much of the focus on cancer as a metabolic disorder gained interest within the past two decades primarily due to advances in metabolomics [1027]. In addition to the glucose metabolic phenotype (in most cancers), other metabolic phenotypes have emerged from metabolomic investigations in most cancers (e.g., polyamines, serine, lactate), and in myc-dependent cancers (e.g., glutamine) [1027]. This paved the way to discovering oncometabolites, endogenous metabolites that cause further malignancy without the initial imposition of chronic tissue dysfunction and whose accumulation initiates and sustains tumors [1027, 1030]. These oncometabolites result from or are used for the three major metabolic pathways [1027]. Fumarate (in renal cell carcinoma), succinate (in paraganglioma), D-2-hydroxyglutarate (in gliomas), choline (in breast cancer, prostate cancer), glycine (in breast cancer), asparagine (in leukemia), and sarcosine (in prostate cancer) are other examples of oncometabolites [1030]. Some cancers seem to exploit aerobic glycolysis, some exploit glutaminolysis, while others use a combination of multiple energy sources [19, 1027]. These investigations have also led to questions regarding the role of mitochondria and mitochondrial DNA (mtDNA) in the origin and progression of cancer [181]. It has been reported that abnormalities in mitochondria structure and function can give rise to malignancies [181]. Nevertheless, we are far from a complete understanding of the interconnectedness of the host of genetic and epigenetic modifications that give way to the tremendous heterogeneity of cancer metabolic phenotypes [456] [1026].
New insights into the metabolism of Th17 cells
Published in Immunological Medicine, 2023
Besides glycolysis, glutaminolysis also has a vital role in energy production in proliferating cells, including T cells [13]. Th17 cells depend more on glycolysis than other T cell subsets [74]. SLC1A5, known as alanine-serine-cysteine transporter 2 (ASCT2), transports neutral amino acids, including glutamine [75]. Deletion of Slc1a5 leads to impaired Th1 and Th17 cell differentiation [75]. Glutaminase is the first enzyme involved in glutaminolysis, converting glutamine to glutamate. ICER also binds to the promoter region of glutaminase 1 and enhances its expression (Figure 1) [74]. The glutaminase 1 inhibitor, Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES), reduces Th17 cell differentiation and disease activity of MRL/lpr mice and EAE models [74,76]. Glutaminase 2 is another isoenzyme of glutaminase. Glutaminase 2 expression is reduced in CD4 T cells from MRL/lpr and patients with SLE [77]. Glutaminase 2 reduces ROS levels in T cells and promotes IL-2 production, which is reduced in lupus T cells [77]. Glutamate oxaloacetate transaminase 1 (GOT1) converts glutamate to α-ketoglutarate. Inhibition of GOT1 with aminooxy acetic acid (AOA) treatment or short hairpin RNA (shRNA) knockdown decreases Th17 differentiation of murine T cells [78] AOA treatment or adoptive transfer of Got1 knockdown Th17-polarized T cells ameliorates EAE [78].
Modulations of ferroptosis in lung cancer therapy
Published in Expert Opinion on Therapeutic Targets, 2022
Robert Walters, Shaker A. Mousa
Distinct mitochondrial changes occur during ferroptosis, including mitochondrial rupture, increased mitochondrial membrane density, decrease or absence of mitochondrial cristae, and decreased mitochondrial ridges [11,32]. Important factors for glutaminolysis are mitochondrial TCA cycle and decomposition of glutamine. In the absence of glutamine, cysteine-deprived ferroptosis induction is inhibited [5]. Fumarate hydratase, involved in the mitochondrial TCA cycle, is a mitochondrial tumor suppressor and loss of its function has led to ferroptosis resistance of cancer cells [33]. Free Fe2 + is used in lipid peroxidation in the mitochondria in the forms of heme and iron-sulfur clusters. CDGSH iron sulfur domain 1 (CISD1) is a mitochondrial outer membrane protein that can inhibit the lipid peroxidation in the mitochondria [11]. Pioglitazone, an anti-diabetic medication, and RNA therapy can be used to inhibit CISD1 and further inhibit mitochondrial iron uptake to prevent mitochondrial lipid peroxidation and induction of ferroptosis [34]. Erastin has been shown to interact with voltage-dependent anion channels (VDACs), which induced mitochondrial dysfunction, release of oxides, and ferroptosis [35]. Overall, the mitochondria is one of the most important organelles in ferroptosis and plays a crucial role in its regulation.
Therapeutic perspectives on the metabolism of lymphocytes in patients with rheumatoid arthritis and systemic lupus erythematosus
Published in Expert Review of Clinical Immunology, 2021
Amino acid metabolism plays an important role in immune cell activation, differentiation, and function. Amino acids are required not only for protein synthesis, but also for various cellular processes underlying inflammation, such as nucleic acid synthesis, regulation of mTORC1 signaling, and control of stress pathways [39,40]. Glutamine is a non-essential amino acid abundant in the circulatory system whose consumption is increased in activated T cells [28]. In glutaminolysis, glutamine is first hydrolyzed to glutamate and then to α-ketoglutarate which is an intermediate in the TCA cycle and a substrate for histone demethylases and DNA demethylases [41]. Glutamine deficiency [2,42] or inhibition of α-ketoglutarate [43] promotes Treg cell differentiation. Glutaminase, the first enzyme in the glutaminolytic pathway, is transcriptionally induced by ICER to promote Th17 cell differentiation. Inhibition of glutaminase suppresses Th17 cell differentiation, promotes Th1 cell differentiation, and has no effect on Treg cell differentiation [44].