bims-glucam 2024-06-30 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2024–06–30
seventeen papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutaminase - A potential target for cancer treatment.
SIRT4 Has an Anti-Cancer Role in Cervical Cancer by Inhibiting Glutamine Metabolism via the MEK/ERK/C-Myc Axis.
GLS and GLS2 Glutaminase Isoenzymes in the Antioxidant System of Cancer Cells.
Altered Metabolic Signaling and Potential Therapies in Polyglutamine Diseases.
Terpinen-4-ol Improves Lipopolysaccharide-Induced Macrophage Inflammation by Regulating Glutamine Metabolism.
PCK2 maintains intestinal homeostasis and prevents colitis by protecting antibody-secreting cells from oxidative stress.
Modeling of cell cultivation for monoclonal antibody production processes considering lactate metabolic shifts.
Causal effects of circulating glutamine on colitis, IBD, and digestive system cancers: a Mendelian randomisation study.
Stable Isotope Tracing Analysis in Cancer Research: Advancements and Challenges in Identifying Dysregulated Cancer Metabolism and Treatment Strategies.
Influence of the glutamate-glutamine cycle on valproic acid-associated hepatotoxicity in pediatric patients with epilepsy.
The Role of Oxidative Metabolism in Tumorigenesis and Drug Resistance.
Replenishment of TCA cycle intermediates and long-noncoding RNAs regulation in breast cancer.
Glutathione Dynamics in the Tumor Microenvironment: A Potential Target of Cancer Stem Cells and T Cells.
Metabolism and Nutrition of L-Glutamate and L-Glutamine in Ruminants.
Metabolic reprogramming of the tumor microenvironment to enhance immunotherapy.
Myc upregulates Ggct, γ-glutamylcyclotransferase to promote development of p53-deficient osteosarcoma.
Immunometabolic characteristics of Dendritic Cells and its significant modulation by mitochondria-associated signaling in the tumor microenvironment influence cancer progression.

Biomedicine (Taipei). 2024 ;14(2): 29-37

Glutaminase - A potential target for cancer treatment.

Josephine Anthony, Sureka Varalakshmi, Ashok Kumar Sekar, Nalini Devarajan, Balamurugan Janakiraman, Rajendran Peramaiyan.

  The overexpression of glutaminase is reported to influence cancer growth and metastasis through glutaminolysis. Upregulation of glutamine catabolism is recently recognized as a critical feature of cancer, and cancer cells are observed to reprogram glutamine metabolism to maintain its survival and proliferation. Special focus is given on the glutaminase isoform, GLS1 (kidney type glutaminase), as the other isoform GLS2 (Liver type glutaminase) acts as a tumour suppressor in some conditions. Glutaminolysis linked with autophagy, which is mediated via mTORC1, also serves as a promising target for cancer therapy. Glutamine also plays a vital role in maintaining redox homeostasis. Inhibition of glutaminase aggravates oxidative stress by reducing glutathione level, thus leading to apoptotic-mediated cell death in cancer cells Therefore, inhibiting the glutaminase activity using glutaminase inhibitors such as BPTES, DON, JHU-083, CB-839, compound 968, etc. may answer many intriguing questions behind the uncontrolled proliferation of cancer cells and serve as a prophylactic treatment for cancer. Earlier reports neither discuss nor provide perspectives on exact signaling gene or pathway. Hence, the present review highlights the plausible role of glutaminase in cancer and the current therapeutic approaches and clinical trials to target and inhibit glutaminase enzymes for better cancer treatment.

Keywords:  Autophagy; Cancer; Glutaminase; Glutaminase inhibitor; Glutamine; Redox homeostasis

DOI:  https://doi.org/10.37796/2211-8039.1445
Anticancer Res. 2024 Jul;44(7): 2861-2870

SIRT4 Has an Anti-Cancer Role in Cervical Cancer by Inhibiting Glutamine Metabolism via the MEK/ERK/C-Myc Axis.

Yina Zhang, Xiaocen Niu, Yuanhe Wang, Shuting Bao, Peiyue Jiang, Xiaorui Dong.

   BACKGROUND/AIM: Glutamine metabolism is crucial in cell proliferation, aging, and apoptosis across various cancer types. Existing research indicates that Sirtuin 4 (SIRT4), primarily located in mitochondria, modulates this process. This study aimed to clarify the regulatory relationship between SIRT4 and glutamine metabolism in cervical cancer.
MATERIALS AND METHODS: SIRT4 mRNA levels and their clinical correlation to cervical cancer were analyzed using the UALCAN database. Immunohistochemistry (IHC) was performed to assess SIRT4 protein expression in tissue samples from cervical cancer patients. Transient transfection was employed to create Hela and Siha cell lines with overexpressed SIRT4, mitogen-activated extracellular signal-regulated kinase (MEK), and glutaminase 1 (GLS1). The impact on cellular functions was studied using MTT, soft agar, transwell, and western blotting assays. Glutamate and ATP levels were also measured to evaluate metabolic changes.
RESULTS: Low levels of SIRT4 mRNA in cervical cancer tissues correlated with tumor metastasis and poor survival rates. Overexpression of SIRT4 led to suppressed cell proliferation, colony growth, and motility, along with significant down-regulation of GLS expression, a key contributor to glutamine metabolism. Additionally, SIRT4 overexpression resulted in the inactivation of the MEK/ERK/c-myc signaling pathway, while overexpression of MEK reversed these effects. Notably, the inhibitory effects of SIRT4 on cell proliferation, colony formation, migration, and invasion in Hela and Siha cells were significantly attenuated following GLS1 overexpression.
CONCLUSION: SIRT4 acts as an anti-cancer agent in cervical cancer by inhibiting glutamine metabolism through the MEK/ERK/c-myc signaling pathway, providing a novel sight for cervical cancer therapy.

Keywords:  MEK/ERK/c-myc signal; SIRT4; cervical cancer; glutamine metabolism

DOI:  https://doi.org/10.21873/anticanres.17098
Antioxidants (Basel). 2024 Jun 20. pii: 745. [Epub ahead of print]13(6):

GLS and GLS2 Glutaminase Isoenzymes in the Antioxidant System of Cancer Cells.

Juan De Los Santos-Jiménez, José A Campos-Sandoval, Francisco J Alonso, Javier Márquez, José M Matés.

  A pathway frequently altered in cancer is glutaminolysis, whereby glutaminase (GA) catalyzes the main step as follows: the deamidation of glutamine to form glutamate and ammonium. There are two types of GA isozymes, named GLS and GLS2, which differ considerably in their expression patterns and can even perform opposing roles in cancer. GLS correlates with tumor growth and proliferation, while GLS2 can function as a context-dependent tumor suppressor. However, both isoenzymes have been described as essential molecules handling oxidant stress because of their involvement in glutathione production. We reviewed the literature to highlight the critical roles of GLS and GLS2 in restraining ROS and regulating both cellular signaling and metabolic stress due to their function as indirect antioxidant enzymes, as well as by modulating both reductive carboxylation and ferroptosis. Blocking GA activity appears to be a potential strategy in the dual activation of ferroptosis and inhibition of cancer cell growth in a ROS-mediated mechanism.

Keywords:  ROS; cancer; ferroptosis; glutaminase; glutaminolysis; glutathione; metabolic reprogramming; oxidative stress

DOI:  https://doi.org/10.3390/antiox13060745
Metabolites. 2024 May 31. pii: 320. [Epub ahead of print]14(6):

Altered Metabolic Signaling and Potential Therapies in Polyglutamine Diseases.

Alisha Vohra, Patrick Keefe, Prasanth Puthanveetil.

  Polyglutamine diseases comprise a cluster of genetic disorders involving neurodegeneration and movement disabilities. In polyglutamine diseases, the target proteins become aberrated due to polyglutamine repeat formation. These aberrant proteins form the root cause of associated complications. The metabolic regulation during polyglutamine diseases is not well studied and needs more attention. We have brought to light the significance of regulating glutamine metabolism during polyglutamine diseases, which could help in decreasing the neuronal damage associated with excess glutamate and nucleotide generation. Most polyglutamine diseases are accompanied by symptoms that occur due to excess glutamate and nucleotide accumulation. Along with a dysregulated glutamine metabolism, the Nicotinamide adenine dinucleotide (NAD+) levels drop down, and, under these conditions, NAD+ supplementation is the only achievable strategy. NAD+ is a major co-factor in the glutamine metabolic pathway, and it helps in maintaining neuronal homeostasis. Thus, strategies to decrease excess glutamate and nucleotide generation, as well as channelizing glutamine toward the generation of ATP and the maintenance of NAD+ homeostasis, could aid in neuronal health. Along with understanding the metabolic dysregulation that occurs during polyglutamine diseases, we have also focused on potential therapeutic strategies that could provide direct benefits or could restore metabolic homeostasis. Our review will shed light into unique metabolic causes and into ideal therapeutic strategies for treating complications associated with polyglutamine diseases.

Keywords:  NAD+ regulation; metabolic signaling; neuronal health; polyglutamine diseases; therapeutics

DOI:  https://doi.org/10.3390/metabo14060320
Foods. 2024 Jun 12. pii: 1842. [Epub ahead of print]13(12):

Terpinen-4-ol Improves Lipopolysaccharide-Induced Macrophage Inflammation by Regulating Glutamine Metabolism.

Yanhui Liu, Xin Tang, Huazhen Zhang, Linyan Zheng, Ping Lai, Chang Guo, Jingfan Ma, Hongbo Chen, Longxin Qiu.

  Terpinen-4-ol (T-4-O) is an important component of tea tree oil and has anti-inflammatory effects. Currently, there are very few studies on the mechanisms by which T-4-O improves lipopolysaccharide (LPS)-induced macrophage inflammation. In this study, LPS-stimulated mouse RAW264.7 macrophages were used as a model to analyze the effects of T-4-O on macrophage inflammatory factors and related metabolic pathways in an inflammatory environment. The results showed that T-4-O significantly decreased the expression levels of inflammatory cytokines induced by LPS. Cellular metabolism results showed that T-4-O significantly decreased the ratio of the extracellular acidification rate and oxygen consumption rate. Non-targeted metabolomics results showed that T-4-O mainly affected glutamine and glutamate metabolism and glycine, serine, and threonine metabolic pathways. qPCR results showed that T-4-O increased the transcript levels of GLS and GDH and promoted glutamine catabolism. Western blotting results showed that T-4-O inhibited the mTOR and IκB, thereby decreasing NF-κB activity. The overall results showed that T-4-O inhibited mTOR phosphorylation to promote glutamine metabolism and increased cell oxidative phosphorylation levels, thereby inhibiting the expression of LPS-induced inflammatory cytokines.

Keywords:  glutamine; inflammatory cytokines; lipopolysaccharide (LPS); non-targeted metabolomics; terpinen-4-ol

DOI:  https://doi.org/10.3390/foods13121842
Immunology. 2024 Jun 27.

PCK2 maintains intestinal homeostasis and prevents colitis by protecting antibody-secreting cells from oxidative stress.

Kun-Long Duan, Tian-Xiang Wang, Jian-Wei You, Hai-Ning Wang, Zhi-Qiang Wang, Zi-Xuan Huang, Jin-Ye Zhang, Yi-Ping Sun, Yue Xiong, Kun-Liang Guan, Dan Ye, Li Chen, Ronghua Liu, Hai-Xin Yuan.

  Maintaining intracellular redox balance is essential for the survival, antibody secretion, and mucosal immune homeostasis of immunoglobulin A (IgA) antibody-secreting cells (ASCs). However, the relationship between mitochondrial metabolic enzymes and the redox balance in ASCs has yet to be comprehensively studied. Our study unveils the pivotal role of mitochondrial enzyme PCK2 in regulating ASCs' redox balance and intestinal homeostasis. We discover that PCK2 loss, whether globally or in B cells, exacerbates dextran sodium sulphate (DSS)-induced colitis due to increased IgA ASC cell death and diminished antibody production. Mechanistically, the absence of PCK2 diverts glutamine into the TCA cycle, leading to heightened TCA flux and excessive mitochondrial reactive oxygen species (mtROS) production. In addition, PCK2 loss reduces glutamine availability for glutathione (GSH) synthesis, resulting in a decrease of total glutathione level. The elevated mtROS and reduced GSH expose ASCs to overwhelming oxidative stress, culminating in cell apoptosis. Crucially, we found that the mitochondria-targeted antioxidant Mitoquinone (Mito-Q) can mitigate the detrimental effects of PCK2 deficiency in IgA ASCs, thereby alleviating colitis in mice. Our findings highlight PCK2 as a key player in IgA ASC survival and provide a potential new target for colitis treatment.

Keywords:  B cell; mucosal immunology; reactive oxygen species

DOI:  https://doi.org/10.1111/imm.13827
Biotechnol Prog. 2024 Jun 24. e3486

Modeling of cell cultivation for monoclonal antibody production processes considering lactate metabolic shifts.

Kozue Okamura, Sara Badr, Yusuke Ichida, Akira Yamada, Hirokazu Sugiyama.

  Demand for monoclonal antibodies (mAbs) is rapidly increasing. To achieve higher productivity, there have been improvements to cell lines, operating modes, media, and cultivation conditions. Representative mathematical models are needed to narrow down the growing number of process alternatives. Previous studies have proposed mechanistic models to depict cell metabolic shifts (e.g., lactate production to consumption). However, the impacts of variations of some operating conditions have not yet been fully incorporated in such models. This paper offers a new mechanistic model considering variations in dissolved oxygen and glutamine depletion on cell metabolism applied to a novel Chinese hamster ovary (CHO) cell line. Expressions for the specific rates of lactate production, glutamine consumption, and mAb production were formulated for stirred and shaken-tank reactors. A deeper understanding of lactate metabolic shifts was obtained under different combinations of experimental conditions. Lactate consumption was more pronounced in conditions with higher DO and low glutamine concentrations. The model offers mechanistic insights that are useful for designing advanced operation strategies. It can be used in design space generation and process optimization for better productivity and product quality.

Keywords:  Chinese hamster ovary cells; dissolved oxygen; glutamine; lactate metabolic shifts; mechanistic model; orbitally‐shaken tanks; process design

DOI:  https://doi.org/10.1002/btpr.3486
J Cancer. 2024 ;15(12): 3738-3749

Causal effects of circulating glutamine on colitis, IBD, and digestive system cancers: a Mendelian randomisation study.

Yang Xie, Yonghui Wu, Qing Tao, Youxiang Chen, Chunyan Zeng.

  Backgrounds: There is growing evidence linking glutamine levels to the risk of gastrointestinal diseases, yet the presence of a causal relationship remains uncertain. In this study, we employed a Mendelian randomization (MR) approach to investigate potential causal associations between glutamine and colitis, inflammatory bowel disease (IBD), and digestive tumors. Methods: Genetic instrumental variables for glutamine exposure were identified from a genome-wide association study (GWAS) involving 114,751 participants. We pooled statistics from GWAS of gastrointestinal diseases in European populations, encompassing colitis (cases=1193, controls=461,740), IBD (cases=31,665, controls=33,977), Crohn's disease (cases=17,897, controls=33,977), ulcerative colitis (cases=1,239, controls=990), oesophageal cancer (cases=740, controls=372,016), gastric cancer (cases=6,563, controls=195,745), liver cell carcinoma (cases=168, controls=372,016), hepatic bile duct cancer (cases=418, controls=159,201), pancreatic cancer (cases=1,196, controls=475,049), and colon cancer (cases=1,494, controls=461,439). To ensure the validity of our findings, we utilized several analytical approaches including inverse variance weighted, weighted median, weighted mode, MR-Egger, and simple mode method. Results: Using the IVW method, we found that glutamine levels were inversely associated with colon cancer (OR = 0.998; 95% CI: 0.997-1.000; P = 0.027), colitis (OR = 0.998; 95% CI: 0.997-1.000; P = 0.020), and IBD (OR = 0.551; 95% CI: 0.343-0.886; P = 0.014). Subgroup analysis revealed a negative association between glutamine and Crohn's disease (OR = 0.375; 95% CI: 0.253-0.557; P = 1.11E-06), but not with ulcerative colitis (OR = 0.508; 95% CI: 0.163-1.586; P = 0.244). Glutamine levels showed no significant correlation with oesophageal cancer (OR = 1.000; 95% CI: 0.999-1.001; P = 0.566), gastric cancer (OR = 0.966; 95% CI: 0.832-1.121; P = 0.648), liver cell carcinoma (OR = 1.000; 95% CI: 0.999-1.000; P = 0.397), hepatic bile duct cancer (OR = 0.819; 95% CI: 0.499-1.344; P = 0.430), and pancreatic cancer (OR = 1.130; 95% CI: 0.897-1.423; P = 0.301). Sensitivity analyses also supports this finding, affirming the reliability and robustness of our study. Conclusions: This study suggests that blood glutamine levels in European populations may lower the risk of colon cancer, colitis, and IBD, particularly Crohn's disease. Nevertheless, additional research involving a diverse range of ancestries is imperative to corroborate this causal relationship.

Keywords:  Colitis; Digestive tumors; GWAS; IBD; Mendelian randomization; circulating glutamine

DOI:  https://doi.org/10.7150/jca.96085
Metabolites. 2024 May 31. pii: 318. [Epub ahead of print]14(6):

Stable Isotope Tracing Analysis in Cancer Research: Advancements and Challenges in Identifying Dysregulated Cancer Metabolism and Treatment Strategies.

Dalton Hilovsky, Joshua Hartsell, Jamey D Young, Xiaojing Liu.

  Metabolic reprogramming is a hallmark of cancer, driving the development of therapies targeting cancer metabolism. Stable isotope tracing has emerged as a widely adopted tool for monitoring cancer metabolism both in vitro and in vivo. Advances in instrumentation and the development of new tracers, metabolite databases, and data analysis tools have expanded the scope of cancer metabolism studies across these scales. In this review, we explore the latest advancements in metabolic analysis, spanning from experimental design in stable isotope-labeling metabolomics to sophisticated data analysis techniques. We highlight successful applications in cancer research, particularly focusing on ongoing clinical trials utilizing stable isotope tracing to characterize disease progression, treatment responses, and potential mechanisms of resistance to anticancer therapies. Furthermore, we outline key challenges and discuss potential strategies to address them, aiming to enhance our understanding of the biochemical basis of cancer metabolism.

Keywords:  cancer metabolism; high resolution mass spectrometry; stable isotope tracing

DOI:  https://doi.org/10.3390/metabo14060318
Clin Toxicol (Phila). 2024 Jun 24. 1-8

Influence of the glutamate-glutamine cycle on valproic acid-associated hepatotoxicity in pediatric patients with epilepsy.

Linfeng Ma, Jingwei Zhu, Xiaoni Kong, Li Chen, Jiangdong Du, Liping Yang, Dan Wang, Zhe Wang.

   INTRODUCTION: Although valproic acid is generally well tolerated, hepatotoxicity is a common side effect in patients receiving long-term treatment. However, the mechanisms underlying valproic acid-associated hepatotoxicity remain elusive.
METHODS: To investigate the mechanisms and explore the potential risk factors for valproic acid-associated hepatotoxicity, 165 age-matched pediatric patients were recruited for laboratory tests and glutamate-glutamine cycle analysis.
RESULTS: The concentration of glutamate in patients with hepatotoxicity was significantly greater than that in control patients, while the concentration of glutamine in patients with hepatotoxicity was significantly lower than that in control patients (P ˂ 0.05). In addition, the frequencies of the heterozygous with one mutant allele and homozygous with two mutant alleles genotypes in glutamate-ammonia ligase rs10911021 were significantly higher in the hepatotoxicity group than those in the control group (47.1 percent versus 32.5 percent, P = 0.010; 17.6 percent versus 5.2 percent, P = 0.001, respectively). Moreover, heterozygous carriers with one mutant allele and homozygous carriers with two mutant alleles genotypes of glutamate-ammonia ligase rs10911021 exhibited significant differences in the concentrations of glutamine and glutamate concentrations (P ˂ 0.001 and P = 0.001, respectively) and liver function indicators (activities of aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase, P ˂ 0.001, respectively). Furthermore, logistic regression analysis indicated that glutamate-ammonia ligase rs10911021 (P = 0.002, odds ratio: 3.027, 95 percent confidence interval, 1.521 - 6.023) and glutamate (P = 0.001, odds ratio: 2.235, 95 percent confidence interval, 1.369 - 3.146) were associated with a greater risk for hepatotoxicity, while glutamine concentrations were negatively associated with hepatotoxicity (P = 0.001, odds ratio: 0.711, 95 percent confidence interval, 0.629 - 0.804).
DISCUSSION: Understanding pharmacogenomic risks for valproic acid induced hepatotoxicity might help direct patient specific care. Limitations of our study include the exclusive use of children from one location and concomitant medication use in many patients.
CONCLUSION: Perturbation of the glutamate-glutamine cycle is associated with valproic acid-associated hepatotoxicity. Moreover, glutamate-ammonia ligase rs10911021, glutamate and glutamine concentrations are potential risk factors for valproic acid-associated hepatotoxicity.

Keywords:  Valproic acid; glutamate; glutamine; glutamine synthetase; hepatotoxicity

DOI:  https://doi.org/10.1080/15563650.2024.2366920
Discov Med. 2024 Jun;36(185): 1109-1126

The Role of Oxidative Metabolism in Tumorigenesis and Drug Resistance.

Fabrizio Marcucci, Cristiano Rumio.

  Aerobic glycolysis, i.e., non-oxidative glycolysis occurring under aerobic conditions (the so-called Warburg effect) is now recognized as a hallmark of cancer. However, evidence increasingly indicates that upregulated oxidative metabolism is also pivotal in tumorigenesis. In this article, we discuss factors that upregulate oxidative metabolism in tumor cells. These factors are associated with tumor cell-intrinsic and -extrinsic stimuli including antitumor drugs, requirements related to the different steps of tumorigenesis (initiation and acquisition of cancer stem-like cell functions, primary tumor growth, quiescence, metastatic dissemination), factors related to the phenotypic changes of tumor cells (e.g., autophagy and epithelial-mesenchymal transition), and particular metabolic requirements of proliferating tumor cells. In this context, we also discuss drug resistance associated with upregulated oxidative metabolism. We conclude by proposing a model whereby these factors, either individually or in combination, promote upregulation of oxidative metabolism. In the following, we address some mechanistic aspects that underlie the upregulation of oxidative metabolism and discuss the consequences on tumor prognosis. In the conclusion section of this article, we discuss possible therapeutic implications of the knowledge gathered in this field over the years.

Keywords:  drug resistance; lactogenesis; metastasis; oxidative metabolism; tumor growth; tumor initiation

DOI:  https://doi.org/10.24976/Discov.Med.202436185.102
Mol Cell Endocrinol. 2024 Jun 25. pii: S0303-7207(24)00177-1. [Epub ahead of print] 112321

Replenishment of TCA cycle intermediates and long-noncoding RNAs regulation in breast cancer.

Xuewei Zheng, ShunShun Zhang, HaoDi Ma, Yirui Dong, Jiayu Zheng, Li Zeng, Jiangbo Liu, Yanzhenzi Dai, Qinan Yin.

  The tricarboxylic acid (TCA) cycle is an essential interface that coordinates cellular metabolism and is as a primary route determining the fate of a variety of fuel sources, including glucose, fatty acid and glutamate. The crosstalk of nutrients replenished TCA cycle regulates breast cancer (BC) progression by changing substrate levels-induced epigenetic alterations, especially the methylation, acetylation, succinylation and lactylation. Long non-coding RNAs (lncRNA) have dual roles in inhibiting or promoting energy reprogramming, and so altering the metabolic flux of fuel sources to the TCA cycle, which may regulate epigenetic modifications at the cellular level of BC. This narrative review discussed the central role of the TCA cycle in interconnecting numerous fuels and the induced epigenetic modifications, and the underlying regulatory mechanisms of lncRNAs in BC.

Keywords:  Epigenetic modifications; TCA cycle; breast cancer; long-noncoding RNAs

DOI:  https://doi.org/10.1016/j.mce.2024.112321
Int J Stem Cells. 2024 Jun 26.

Glutathione Dynamics in the Tumor Microenvironment: A Potential Target of Cancer Stem Cells and T Cells.

Youngjun Park, Eui Man Jeong.

  Glutathione (GSH), the main cellular antioxidant, dynamically influences tumor growth, metastasis, and resistance to therapy in the tumor microenvironment (TME), which comprises cancer cells, immune cells, stromal cells, and non-cellular components, including the extracellular matrix, metabolites, hypoxia, and acidity. Cancer stem cells (CSCs) and T cells are minor but significant cell subsets of the TME. GSH dynamics influences the fate of CSCs and T cells. Here, we explored GSH dynamics in CSCs and T cells within the TME, as well as therapeutic approaches that could target these dynamics.

Keywords:  Cancer stem cells; Glutathione dynamics; T cells; Tumor microenvironment

DOI:  https://doi.org/10.15283/ijsc24060
Animals (Basel). 2024 Jun 14. pii: 1788. [Epub ahead of print]14(12):

Metabolism and Nutrition of L-Glutamate and L-Glutamine in Ruminants.

Guoyao Wu, Fuller W Bazer, Gregory A Johnson, M Carey Satterfield, Shannon E Washburn.

  Although both L-glutamate (Glu) and L-glutamine (Gln) have long been considered nutritionally nonessential in ruminants, these two amino acids have enormous nutritional and physiological importance. Results of recent studies revealed that extracellular Gln is extensively degraded by ruminal microbes, but extracellular Glu undergoes little catabolism by these cells due to the near absence of its uptake. Ruminal bacteria hydrolyze Gln to Glu plus ammonia and, intracellularly, use both amino acids for protein synthesis. Microbial proteins and dietary Glu enter the small intestine in ruminants. Both Glu and Gln are the major metabolic fuels and building blocks of proteins, as well as substrates for the syntheses of glutathione and amino acids (alanine, ornithine, citrulline, arginine, proline, and aspartate) in the intestinal mucosa. In addition, Gln and aspartate are essential for purine and pyrimidine syntheses, whereas arginine and proline are necessary for the production of nitric oxide (a major vasodilator) and collagen (the most abundant protein in the body), respectively. Under normal feeding conditions, all diet- and rumen-derived Glu and Gln are extensively utilized by the small intestine and do not enter the portal circulation. Thus, de novo synthesis (e.g., from branched-chain amino acids and α-ketoglutarate) plays a crucial role in the homeostasis of Glu and Gln in the whole body but may be insufficient for maximal growth performance, production (e.g., lactation and pregnancy), and optimal health (particularly intestinal health) in ruminants. This applies to all types of feeding systems used around the world (e.g., rearing on a milk replacer before weaning, pasture-based production, and total mixed rations). Dietary supplementation with the appropriate doses of Glu or Gln [e.g., 0.5 or 1 g/kg body weight (BW)/day, respectively] can safely improve the digestive, endocrine, and reproduction functions of ruminants to enhance their productivity. Both Glu and Gln are truly functional amino acids in the nutrition of ruminants and hold great promise for improving their health and productivity.

Keywords:  amino acids; glutamate; glutamine; health; metabolism; nutrition; ruminants

DOI:  https://doi.org/10.3390/ani14121788
BMB Rep. 2024 Jun 26. pii: 6203. [Epub ahead of print]

Metabolic reprogramming of the tumor microenvironment to enhance immunotherapy.

Seon Ah Lim.

Immunotherapy represents a promising treatment strategy for targeting various tumor types. However, the overall response rate is low due to the tumor microenvironment (TME). In the TME, numerous distinct factors actively induce immunosuppression, restricting the efficacy of anticancer immune reactions. Recently, metabolic reprogramming of tumors has been recognized for its role in modulating the tumor microenvironment to enhance immune cell responses in the TME. Furthermore, recent elucidations underscore the critical role of metabolic limitations imposed by the tumor microenvironment on the effectiveness of antitumor immune cells, guiding the development of novel immunotherapeutic approaches. Hence, achieving a comprehensive understanding of the metabolic requirements of both cancer and immune cells within the TME is pivotal. This insight not only aids in acknowledging the current limitations of clinical practices but also significantly shapes the trajectory of future research endeavors in the domain of cancer immunotherapy. In addition, therapeutic interventions targeting metabolic limitations have exhibited promising potential as combinatory treatments across diverse cancer types. In this review, we first discuss the metabolic barriers in the TME. Second, we explore how the immune response is regulated by metabolites. Finally, we will review the current strategy for targeting metabolism to not simply inhibit tumor growth but also enhance antitumor immune responses. Thus, we could suggest potent combination therapy for improving immunotherapy with metabolic inhibitors.
Cancer Sci. 2024 Jun 26.

Myc upregulates Ggct, γ-glutamylcyclotransferase to promote development of p53-deficient osteosarcoma.

Tomoya Ueno, Shohei Otani, Yuki Date, Yu Katsuma, Yuma Nagayoshi, Tomoko Ito, Hiromi Ii, Susumu Kageyama, Susumu Nakata, Kosei Ito.

  Osteosarcoma (OS) in humans is characterized by alterations in the TP53 gene. In mice, loss of p53 triggers OS development, for which c-Myc (Myc) oncogenicity is indispensable. However, little is known about which genes are targeted by Myc to promote tumorigenesis. Here, we examined the role of γ-glutamylcyclotransferase (Ggct) which is a component enzyme of the γ-glutamyl cycle essential for glutathione homeostasis, in human and mouse OS development. We found that GGCT is a poor prognostic factor for human OS, and that deletion of Ggct suppresses p53-deficient osteosarcomagenesis in mice. Myc upregulates Ggct directly by binding to the Ggct promoter, and deletion of a Myc binding site therein by genome editing attenuated the tumorigenic potential of p53-deficient OS cells. Taken together, these results show a rationale that GGCT is widely upregulated in cancer cells and solidify its suitability as a target for anticancer drugs.

Keywords:  Ggct; Myc; glutathione; osteosarcoma; p53

DOI:  https://doi.org/10.1111/cas.16255
Biochem Biophys Res Commun. 2024 Jun 14. pii: S0006-291X(24)00804-0. [Epub ahead of print]726 150268

Immunometabolic characteristics of Dendritic Cells and its significant modulation by mitochondria-associated signaling in the tumor microenvironment influence cancer progression.

Sayak Ghosh, Rittick Dutta, Debapriya Ghatak, Devyani Goswami, Rudranil De.

  Dendritic cells (DCs) mediated T-cell responses is critical to anti-tumor immunity. This study explores immunometabolic attributes of DC, emphasizing on mitochondrial association, in Tumor Microenvironment (TME) that regulate cancer progression. Conventional DC subtypes cross-present tumor-associated antigens to activate lymphocytes. However, plasmacytoid DCs participate in both pro- and anti-tumor signaling where mitochondrial reactive oxygen species (mtROS) play crucial role. CTLA-4, CD-47 and other surface-receptors of DC negatively regulates T-cell. Increased glycolysis-mediated mitochondrial citrate buildup and translocation to cytosol with augmented NADPH, enhances mitochondrial fatty acid synthesis fueling DCs. Different DC subtypes and stages, exhibit variable mitochondrial content, membrane potential, structural dynamics and bioenergetic metabolism regulated by various cytokine stimulation, e.g., GM-CSF, IL-4, etc. CD8α+ cDC1s augmented oxidative phosphorylation (OXPHOS) which diminishes at advance effector stages. Glutaminolysis in mitochondria supplement energy in DCs but production of kynurenine and other oncometabolites leads to immunosuppression. Mitochondria-associated DAMPs cause activation of cGAS-STING pathway and inflammasome oligomerization stimulating DC and T cells. In this study, through a comprehensive survey and critical analysis of the latest literature, the potential of DC metabolism for more effective tumor therapy is highlighted. This underscores the need for future research to explore specific therapeutic targets and potential drug candidates.

Keywords:  Cancer; Dendritic cells; Immunometabolism; Mitochondria; T cells

DOI:  https://doi.org/10.1016/j.bbrc.2024.150268