bims-glucam 2023-12-24 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2023–12–24
seventeen papers selected by
Sreeparna Banerjee, Middle East Technical University

DON of Hope: Starving Pancreatic Cancer by Glutamine Antagonism.
Role of Glycolytic and Glutamine Metabolism Reprogramming on the Proliferation, Invasion, and Apoptosis Resistance through Modulation of Signaling Pathways in Glioblastoma.
Oxaloacetate as a Holy Grail Adjunctive Treatment in Gliomas: A Revisit to Metabolic Pathway.
Mitochondrial metabolism as a dynamic regulatory hub to malignant transformation and anti-cancer drug resistance.
Beta-Hydroxybutyrate Augments Oxaliplatin-Induced Cytotoxicity by Altering Energy Metabolism in Colorectal Cancer Organoids.
RNA Modifications in Cancer Metabolism and Tumor Microenvironment.
The Role of Tumor Metabolic Reprogramming in Tumor Immunity.
The effect of fructose exposure on amino acid metabolism among Chinese community residents and its possible multi-omics mechanisms.
Extracellular matrix detached cancer cells resist oxidative stress by increasing histone demethylase KDM6 activity.
Liquid chromatography-mass spectrometry-based metabolomics and fluxomics reveals the metabolic alterations in glioma U87MG multicellular tumor spheroids versus two-dimensional cell cultures.
SLC16a6, mTORC1, and Autophagy Regulate Ketone Body Excretion in the Intestinal Cells.
Merlin/NF2 regulates SLC7A11/xCT expression and cell viability under glucose deprivation at high cell density in glioblastoma cells.
Butyrate Alleviates High-Fat-Induced Metabolic Disorders Partially through Increasing Systematic Glutamine.
Nutrient inputs and social metabolic control of T cell fate.
Alterations in cellular metabolism under different grades of glioma staging identified based on a multi-omics analysis strategy.
A Metabolic Axis of Immune Intractability.
Oxidative Stress Induced by Chemotherapy: Evaluation of Glutathione and Its Related Antioxidant Enzyme Dynamics in Patients with Colorectal Cancer.

Cancer Res. 2023 Dec 20.

DON of Hope: Starving Pancreatic Cancer by Glutamine Antagonism.

Ray Pillai, Thales Papagiannakopoulos.

A promising approach to treat solid tumors involves disrupting their reliance on glutamine, a key component for various metabolic processes. Traditional attempts using glutamine inhibitors like 6-diazo-5-oxo-L-norleucine (DON) and CB-839 were unsuccessful, but new hope arises with DRP-104, a pro-drug of DON. This compound effectively targets tumor metabolism while minimizing side effects. In a recent study published in Nature Cancer, Encarnación-Rosado and colleagues demonstrated in pre-clinical models that pancreatic ductal adenocarcinoma (PDAC) responds well to DRP-104, though tumors adapt through the MEK/ERK signaling pathway, which can be countered by the MEK inhibitor trametinib. In a related study, Recouvreux and colleagues found that DON is effective against pancreatic tumors, revealing that PDAC tumors upregulate asparagine synthesis in response to DON, making them susceptible to asparaginase treatment. Both studies underscore the potential of inhibiting glutamine metabolism and adaptive pathways as a promising strategy against PDAC. These findings pave the way for upcoming clinical trials utilizing DRP-104 and similar glutamine antagonists in the battle against solid tumors.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-3954
Int J Mol Sci. 2023 Dec 18. pii: 17633. [Epub ahead of print]24(24):

Role of Glycolytic and Glutamine Metabolism Reprogramming on the Proliferation, Invasion, and Apoptosis Resistance through Modulation of Signaling Pathways in Glioblastoma.

Cristina Trejo-Solis, Daniela Silva-Adaya, Norma Serrano-García, Roxana Magaña-Maldonado, Dolores Jimenez-Farfan, Elizabeth Ferreira-Guerrero, Arturo Cruz-Salgado, Rosa Angelica Castillo-Rodriguez.

  Glioma cells exhibit genetic and metabolic alterations that affect the deregulation of several cellular signal transduction pathways, including those related to glucose metabolism. Moreover, oncogenic signaling pathways induce the expression of metabolic genes, increasing the metabolic enzyme activities and thus the critical biosynthetic pathways to generate nucleotides, amino acids, and fatty acids, which provide energy and metabolic intermediates that are essential to accomplish the biosynthetic needs of glioma cells. In this review, we aim to explore how dysregulated metabolic enzymes and their metabolites from primary metabolism pathways in glioblastoma (GBM) such as glycolysis and glutaminolysis modulate anabolic and catabolic metabolic pathways as well as pro-oncogenic signaling and contribute to the formation, survival, growth, and malignancy of glioma cells. Also, we discuss promising therapeutic strategies by targeting the key players in metabolic regulation. Therefore, the knowledge of metabolic reprogramming is necessary to fully understand the biology of malignant gliomas to improve patient survival significantly.

Keywords:  glioma; glucose; glutamine; metabolism; oncogenic pathways

DOI:  https://doi.org/10.3390/ijms242417633
Cureus. 2023 Nov;15(11): e48821

Oxaloacetate as a Holy Grail Adjunctive Treatment in Gliomas: A Revisit to Metabolic Pathway.

Abdul Samad, Rajaram Samant, K Venkateshwara Rao, Vyom Bhargava, Shahid I Sadique, Rohit Yadav.

  India experiences a significant amount of morbidity and mortality due to gliomas particularly glioblastoma multiforme (GBM), which ranks among the worst cancers. Oxaloacetate (OAA) is a human keto acid that is central to cellular metabolism; it has been recognized by the US FDA for use in GBM patients, triggering a review to revisit the cellular mechanism of its therapeutic action. Various cellular and molecular studies have proposed that instead of fueling the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS), gliomas prefer to use glycolysis (the Warburg effect) to fuel macromolecules for the synthesis of nucleotides, fatty acids, and amino acids for the accelerated mitosis. A study found that oxaloacetate (OAA) inhibits human lactate dehydrogenase A (LDHA) in cancer cells, reversing the Warburg effect. Studies revealed that OAA supplementation reduced Warburg glycolysis, improved neuronal cell bioenergetics, and triggered brain mitochondrial biogenesis, thereby enhancing the efficacy of standard treatment. Similarly, OAA has been found in preclinical investigations to be able to decrease tumor development and survival rates by blocking the conversion of glutamine to alpha-ketoglutarate (alpha-KG) in the TCA cycle and lowering nicotinamide adenine dinucleotide phosphate (NADPH) levels. OAA is a safe adjuvant that has the potential to be an effective therapy in gliomas when combined with temozolomide (TMZ) chemotherapy and routine surgery.

Keywords:  adjunctive therapy; alter warburg effect; glutamate excitotoxicity; oxaloacetate; glioma

DOI:  https://doi.org/10.7759/cureus.48821
Biochem Biophys Res Commun. 2023 Dec 17. pii: S0006-291X(23)01476-6. [Epub ahead of print]694 149382

Mitochondrial metabolism as a dynamic regulatory hub to malignant transformation and anti-cancer drug resistance.

Manendra Singh Tomar, Ashok Kumar, Ashutosh Shrivastava.

  Glycolysis is the fundamental cellular process that permits cancer cells to convert energy and grow anaerobically. Recent developments in molecular biology have made it evident that mitochondrial respiration is critical to tumor growth and treatment response. As the principal organelle of cellular energy conversion, mitochondria can rapidly alter cellular metabolic processes, thereby fueling malignancies and contributing to treatment resistance. This review emphasizes the significance of mitochondrial biogenesis, turnover, DNA copy number, and mutations in bioenergetic system regulation. Tumorigenesis requires an intricate cascade of metabolic pathways that includes rewiring of the tricarboxylic acid (TCA) cycle, electron transport chain and oxidative phosphorylation, supply of intermediate metabolites of the TCA cycle through amino acids, and the interaction between mitochondria and lipid metabolism. Cancer recurrence or resistance to therapy often results from the cooperation of several cellular defense mechanisms, most of which are connected to mitochondria. Many clinical trials are underway to assess the effectiveness of inhibiting mitochondrial respiration as a potential cancer therapeutic. We aim to summarize innovative strategies and therapeutic targets by conducting a comprehensive review of recent studies on the relationship between mitochondrial metabolism, tumor development and therapeutic resistance.

Keywords:  Cancer; Drug resistance; Electron transport chain; Metabolism; Mitochondria; Oxidative phosphorylation; TCA cycle

DOI:  https://doi.org/10.1016/j.bbrc.2023.149382
Cancers (Basel). 2023 Dec 06. pii: 5724. [Epub ahead of print]15(24):

Beta-Hydroxybutyrate Augments Oxaliplatin-Induced Cytotoxicity by Altering Energy Metabolism in Colorectal Cancer Organoids.

Tolga Sever, Ender Berat Ellidokuz, Yasemin Basbinar, Hulya Ellidokuz, Ömer H Yilmaz, Gizem Calibasi-Kocal.

  Deregulation of cellular metabolism has recently emerged as a notable cancer characteristic. This reprogramming of key metabolic pathways supports tumor growth. Targeting cancer metabolism demonstrates the potential for managing colorectal cancer. Beta-hydroxybutyrate (BOHB) acts as an acetyl-CoA source for the tricarboxylic acid (TCA) cycle, possibly redirecting energy metabolic pathways towards the TCA cycle that could enhance sensitivity to oxaliplatin, through the generation of reactive oxygen species (ROS). This study explores the potential of BOHB to enhance oxaliplatin's cytotoxic effect by altering the energy metabolism in colorectal cancer. The study employed advanced in vitro organoid technology, which successfully emulates in vivo physiology. The combination treatment efficacy of BOHB and oxaliplatin was evaluated via cell viability assay. The levels of key proteins involved in energy metabolism, apoptotic pathways, DNA damage markers, and histone acetylation were analyzed via Western Blot. ROS levels were evaluated via flow cytometer. Non-toxic doses of BOHB with oxaliplatin significantly amplified cytotoxicity in colorectal cancer organoids. Treatment with BOHB and/or melatonin resulted in significantly decreased lactate dehydrogenase A and increased mitochondrial carrier protein 2 levels, indicating inhibited aerobic glycolysis and an increased oxidative phosphorylation rate. This metabolic shift induced apoptotic cell death mediated by oxaliplatin, owing to high levels of ROS. Melatonin counteracted this effect by protecting cancer cells from high oxidative stress conditions. BOHB may enhance the efficacy of chemotherapeutics with a similar mechanism of action to oxaliplatin in colorectal cancer treatment. These innovative combinations could improve treatment outcomes for colorectal cancer patients.

Keywords:  beta-hydroxybutyrate; colorectal cancer; metabolic targeted therapy; organoid; oxaliplatin; reactive oxygen species

DOI:  https://doi.org/10.3390/cancers15245724
Cancer Treat Res. 2023 ;190 3-24

RNA Modifications in Cancer Metabolism and Tumor Microenvironment.

Ying Qing, Dong Wu, Xiaolan Deng, Jianjun Chen, Rui Su.

  RNA modifications have recently been recognized as essential posttranscriptional regulators of gene expression in eukaryotes. Investigations over the past decade have revealed that RNA chemical modifications have profound effects on tumor initiation, progression, refractory, and recurrence. Tumor cells are notorious for their robust plasticity in response to the stressful microenvironment and undergo metabolic adaptations to sustain rapid cell proliferation, which is termed as metabolic reprogramming. Meanwhile, cancer-associated metabolic reprogramming leads to substantial alterations of intracellular and extracellular metabolites, which further reshapes the tumor microenvironment (TME). Moreover, cancer cells compete with tumor-infiltrating immune cells for the limited nutrients to maintain their proliferation and function in the TME. In this chapter, we review recent interesting findings on the engagement of epitranscriptomic pathways, especially the ones associated with N6-methyladenosine (m6A), in the regulation of cancer metabolism and the surrounding microenvironment. We also discuss the promising therapeutic approaches targeting RNA modifications for anti-tumor therapy.

Keywords:  Aerobic glycolysis; Amino acid metabolism; Cancer metabolism; Immune cells; Immunotherapy; Lipid metabolism; RNA modification; Tumor microenvironment; m6A

DOI:  https://doi.org/10.1007/978-3-031-45654-1_1
Int J Mol Sci. 2023 Dec 13. pii: 17422. [Epub ahead of print]24(24):

The Role of Tumor Metabolic Reprogramming in Tumor Immunity.

Xianhong Zhang, Weiguo Song, Yue Gao, Yu Zhang, Yuqi Zhao, Shuailin Hao, Ting Ni.

  The occurrence and development of tumors require the metabolic reprogramming of cancer cells, namely the alteration of flux in an autonomous manner via various metabolic pathways to meet increased bioenergetic and biosynthetic demands. Tumor cells consume large quantities of nutrients and produce related metabolites via their metabolism; this leads to the remodeling of the tumor microenvironment (TME) to better support tumor growth. During TME remodeling, the immune cell metabolism and antitumor immune activity are affected. This further leads to the escape of tumor cells from immune surveillance and therefore to abnormal proliferation. This review summarizes the regulatory functions associated with the abnormal biosynthesis and activity of metabolic signaling molecules during the process of tumor metabolic reprogramming. In addition, we provide a comprehensive description of the competition between immune cells and tumor cells for nutrients in the TME, as well as the metabolites required for tumor metabolism, the metabolic signaling pathways involved, and the functionality of the immune cells. Finally, we summarize current research targeted at the development of tumor immunotherapy. We aim to provide new concepts for future investigations of the mechanisms underlying the metabolic reprogramming of tumors and explore the association of these mechanisms with tumor immunity.

Keywords:  immune cells; tumor immunity; tumor metabolism; tumor microenvironment; tumor therapy

DOI:  https://doi.org/10.3390/ijms242417422
Sci Rep. 2023 Dec 19. 13(1): 22704

The effect of fructose exposure on amino acid metabolism among Chinese community residents and its possible multi-omics mechanisms.

Ouyan Rang, Xinru Qin, Yonghong Tang, Lin Cao, Guojuan Li, Xiaocheng Liu, Jing Zhong, Mu Wang.

The consumption of fructose has increased dramaticly during the last few decades, inducing a great increase in the risk of intrahepatic lipid accumulation, hypertriglyceridemia, hyperuricemia and cancer. However, the underlying mechanism has not yet been fully elucidated. Amino acid metabolism may play an important role in the process of the diseases caused by fructose, but there is still a lack of corresponding evidence. In present study, we provide an evidence of how fructose affects amino acids metabolism in 1895 ordinary residents in Chinese community using UPLC-QqQMS based amino acid targeted metabolomics and the underlying mechanism of fructose exposure how interferes with amino acid metabolism related genes and acetylated modification of proteome in the liver of rats model. We found people with high fructose exposure had higher levels of Asa, EtN, Asp, and Glu, and lower levels of 1MHis, PEtN, Arg, Gln, GABA, Aad, Hyl and Cys. The further mechanism study displayed amino acid metabolic genes of Aspa, Cndp1, Dbt, Dmgdh, and toxic metabolites such as N-acetylethanolamines accumulation, interference of urea cycle, as well as acetylated modification of key enzymes in glutamine metabolic network and glutamine derived NEAAs synthesis pathway in liver may play important roles in fructose caused reprogramming in amino acid metabolism. This research provides novel insights of the mechanism of amino acid metabolic disorder caused by fructose and supplies new targets for clinical therapy.

DOI: https://doi.org/10.1038/s41598-023-50069-5
Saudi J Biol Sci. 2024 Jan;31(1): 103871

Extracellular matrix detached cancer cells resist oxidative stress by increasing histone demethylase KDM6 activity.

Mohamed A Alfaleh, Mohammed Razeeth Shait Mohammed, Anwar M Hashem, Turki S Abujamel, Nabil A Alhakamy, Mohammad Imran Khan.

  Epithelial cancer cells rely on the extracellular matrix (ECM) attachment in order to spread to other organs. Detachment from the ECM is necessary for these cells to seed in other locations. When the attachment to the ECM is lost, cellular metabolism undergoes a significant shift from oxidative metabolism to glycolysis. Additionally, the cancer cells become more dependent on glutaminolysis to avoid a specific type of cell death known as anoikis, which is associated with ECM detachment. In our recent study, we observed increased expression of H3K27me3 demethylases, specifically KDM6A/B, in cancer cells that were resistant to anoikis. Since KDM6A/B is known to regulate cellular metabolism, we investigated the effects of suppressing KDM6A/B with GSK-J4 on the metabolic processes in these anoikis-resistant cancer cells. Our results from untargeted metabolomics revealed a profound impact of KDM6A/B inhibition on various metabolic pathways, including glycolysis, methyl histidine, spermine, and glutamate metabolism. Inhibition of KDM6A/B led to elevated reactive oxygen species (ROS) levels and depolarization of mitochondria, while reducing the levels of glutathione, an important antioxidant, by diminishing the intermediates of the glutamate pathway. Glutamate is crucial for maintaining a pool of reduced glutathione. Furthermore, we discovered that KDM6A/B regulates the key glycolytic genes expression like hexokinase, lactate dehydrogenase, and GLUT-1, which are essential for sustaining glycolysis in anoikis-resistant cancer cells. Overall, our findings demonstrated the critical role of KDM6A/B in maintaining glycolysis, glutamate metabolism, and glutathione levels. Inhibition of KDM6A/B disrupts these metabolic processes, leading to increased ROS levels and triggering cell death in anoikis-resistant cancer cells.

Keywords:  Anoikis resistant; Glycolysis; KDM6A/B; Oxidative stress; ROS

DOI:  https://doi.org/10.1016/j.sjbs.2023.103871
Rapid Commun Mass Spectrom. 2024 Jan 30. 38(2): e9670

Liquid chromatography-mass spectrometry-based metabolomics and fluxomics reveals the metabolic alterations in glioma U87MG multicellular tumor spheroids versus two-dimensional cell cultures.

Shanjing Wen, Xinyi Tu, Qingce Zang, Ying Zhu, Limei Li, Ruiping Zhang, Zeper Abliz.

RATIONALE: Multicellular tumor spheroids (MCTSs) that reconstitute the metabolic characteristics of in vivo tumor tissue may facilitate the discovery of molecular biomarkers and effective anticancer therapies. However, little is known about how cancer cells adapt their metabolic changes in complex three-dimensional (3D) microenvironments. Here, using the two-dimensional (2D) cell model as control, the metabolic phenotypes of glioma U87MG multicellular tumor spheroids were systematically investigated based on static metabolomics and dynamic fluxomics analysis.
METHODS: A liquid chromatography-mass spectrometry-based global metabolomics and lipidomics approach was adopted to survey the cellular samples from 2D and 3D culture systems, revealing marked molecular differences between them. Then, by means of metabolomic pathway analysis, the metabolic pathways altered in glioma MCTSs were found using 13 C6 -glucose as a tracer to map the metabolic flux of glycolysis, the tricarboxylic acid (TCA) cycle, de novo nucleotide synthesis, and de novo lipid biosynthesis in the MCTS model.
RESULTS: We found nine metabolic pathways as well as glycerolipid, glycerophospholipid and sphingolipid metabolism to be predominantly altered in glioma MCTSs. The reduced nucleotide metabolism, amino acid metabolism and glutathione metabolism indicated an overall lower cellular activity in MCTSs. Through dynamic fluxomics analysis in the MCTS model, we found that cells cultured in MCTSs exhibited increased glycolysis activity and de novo lipid biosynthesis activity, and decreased the TCA cycle and de novo purine nucleotide biosynthesis activity.
CONCLUSIONS: Our study highlights specific, altered biochemical pathways in MCTSs, emphasizing dysregulation of energy metabolism and lipid metabolism, and offering novel insight into metabolic events in glioma MCTSs.

DOI: https://doi.org/10.1002/rcm.9670
Biology (Basel). 2023 Nov 26. pii: 1467. [Epub ahead of print]12(12):

SLC16a6, mTORC1, and Autophagy Regulate Ketone Body Excretion in the Intestinal Cells.

Takashi Uebanso, Moeka Fukui, Chisato Naito, Takaaki Shimohata, Kazuaki Mawatari, Akira Takahashi.

  Ketone bodies serve several functions in the intestinal epithelium, such as stem cell maintenance, cell proliferation and differentiation, and cancer growth. Nevertheless, there is limited understanding of the mechanisms governing the regulation of intestinal ketone body concentration. In this study, we elucidated the factors responsible for ketone body production and excretion using shRNA-mediated or pharmacological inhibition of specific genes or functions in the intestinal cells. We revealed that a fasting-mimicked culture medium, which excluded glucose, pyruvate, and glutamine, augmented ketone body production and excretion in the Caco2 and HT29 colorectal cells. This effect was attenuated by glucose or glutamine supplementation. On the other hand, the inhibition of the mammalian target of rapamycin complex1 (mTORC1) recovered a fraction of the excreted ketone bodies. In addition, the pharmacological or shbeclin1-mediated inhibition of autophagy suppressed ketone body excretion. The knockdown of basigin, a transmembrane protein responsible for targeting monocarboxylate transporters (MCTs), such as MCT1 and MCT4, suppressed lactic acid and pyruvic acid excretion but increased ketone body excretion. Finally, we found that MCT7 (SLC16a6) knockdown suppressed ketone body excretion. Our findings indicate that the mTORC1-autophagy axis and MCT7 are potential targets to regulate ketone body excretion from the intestinal epithelium.

Keywords:  autophagy; intestinal cell; ketone body; mTORC1; solute carrier family 16 member 6: SLC16a6 (MCT7)

DOI:  https://doi.org/10.3390/biology12121467
J Biochem. 2023 Dec 15. pii: mvad105. [Epub ahead of print]

Merlin/NF2 regulates SLC7A11/xCT expression and cell viability under glucose deprivation at high cell density in glioblastoma cells.

Itsuki Yamaguchi, Hironori Katoh.

  The cystine/glutamate transporter SLC7A11/xCT is highly expressed in many cancer cells and plays an important role in antioxidant activity by supplying cysteine for glutathione synthesis. Under glucose-depleted conditions, however, SLC7A11-mediated cystine uptake causes oxidative stress and cell death called disulfidptosis, a new form of cell death. We previously reported that high cell density (HD) promotes lysosomal degradation of SLC7A11 in glioblastoma cells, allowing them to survive under glucose-depleted conditions. In this study, we found that the neurofibromatosis type 2 gene, Merlin/NF2 is a key regulator of SLC7A11 in glioblastoma cells at HD. Deletion of Merlin increased SLC7A11 protein level and cystine uptake at HD, leading to promotion of cell death under glucose deprivation. Furthermore, HD significantly decreased SLC7A11 mRNA level, which was restored by Merlin deletion. This study suggests that Merlin suppresses glucose deprivation-induced cell death by downregulating SLC7A11 expression in glioblastoma cells at HD.

Keywords:  amino acid transport; cell death; cell density; glioblastoma; transcriptional regulation

DOI:  https://doi.org/10.1093/jb/mvad105
J Agric Food Chem. 2023 Dec 18.

Butyrate Alleviates High-Fat-Induced Metabolic Disorders Partially through Increasing Systematic Glutamine.

Zeyu Fan, Shaonan Wang, Yingying Meng, Chenglong Wen, Meixue Xu, Xiao Li.

  Obesity has emerged as a worldwide epidemic. Both butyrate and glutamine counteract obesity-related metabolic disorders; however, whether and how they synergistically cooperate with each other remains a mystery. In the study, a high-fat diet (HFD, 60% calories from fat) was used to develop a model of obesity-related metabolic disorder and compared with administrated saline and sodium butyrate (SB, 300 mg/kg body weight) daily by gavage. Compared with HFD counterparts, oral administration of SB in mice exhibited significantly reduced body weight and fat mass and decreased hepatic triglyceride content. The targeted mass spectrum revealed that SB restored serum contents of glutamine, which were significantly decreased by HFD. Furthermore, SB significantly elevated the expression of glutamine synthetase (GS, encoded by GLUL) in the liver, accompanied by more enrichment of H3K27ac modifications within its promoter. In summary, the study verified the contribution of elevated glutamine to the beneficial effects of butyrate on metabolic disorders induced by a high-fat diet, providing a novel pathway for understanding how butyrate benefits metabolic homeostasis.

Keywords:  H3K27ac; adipose tissue; butyrate; glutamine; high-fat diet

DOI:  https://doi.org/10.1021/acs.jafc.3c08926
Cell Metab. 2023 Dec 12. pii: S1550-4131(23)00460-6. [Epub ahead of print]

Nutrient inputs and social metabolic control of T cell fate.

Zachary A Bacigalupa, Madelyn D Landis, Jeffrey C Rathmell.

  Cells in multicellular organisms experience diverse neighbors, signals, and evolving physical environments that drive functional and metabolic demands. To maintain proper development and homeostasis while avoiding inappropriate cell proliferation or death, individual cells interact with their neighbors via "social" cues to share and partition available nutrients. Metabolic signals also contribute to cell fate by providing biochemical links between cell-extrinsic signals and available resources. In addition to metabolic checkpoints that sense nutrients and directly supply molecular intermediates for biosynthetic pathways, many metabolites directly signal or provide the basis for post-translational modifications of target proteins and chromatin. In this review, we survey the landscape of T cell nutrient sensing and metabolic signaling that supports proper immunity while avoiding immunodeficiency or autoimmunity. The integration of cell-extrinsic microenvironmental cues with cell-intrinsic metabolic signaling provides a social metabolic control model to integrate cell signaling, metabolism, and fate.

Keywords:  T cells; epigenetics; immunometabolism; metabolic signaling; social control model

DOI:  https://doi.org/10.1016/j.cmet.2023.12.009
Front Endocrinol (Lausanne). 2023 ;14 1292944

Alterations in cellular metabolism under different grades of glioma staging identified based on a multi-omics analysis strategy.

Xianlei Yan, Jinwei Li, Yang Zhang, Cong Liang, Pengcheng Liang, Tao Li, Quan Liu, Xuhui Hui.

  Glioma is a type of brain tumor closely related to abnormal cell metabolism. Firstly, multiple combinatorial sequencing studies have revealed this relationship. Genomic studies have identified gene mutations and gene expression disorders related to the development of gliomas, which affect cell metabolic pathways. In addition, transcriptome studies have revealed the genes and regulatory networks that regulate cell metabolism in glioma tissues. Metabonomics studies have shown that the metabolic pathway of glioma cells has changed, indicating their distinct energy and nutritional requirements. This paper focuses on the retrospective analysis of multiple groups combined with sequencing to analyze the changes in various metabolites during metabolism in patients with glioma. Finally, the changes in genes, regulatory networks, and metabolic pathways regulating cell metabolism in patients with glioma under different metabolic conditions were discussed. It is also proposed that multi-group metabolic analysis is expected to better understand the mechanism of abnormal metabolism of gliomas and provide more personalized methods and guidance for early diagnosis, treatment, and prognosis evaluation of gliomas.

Keywords:  biomarker; cellular metabolism; glioma; multi-omics analysis; single-cell

DOI:  https://doi.org/10.3389/fendo.2023.1292944
Cancer Immunol Res. 2023 Dec 21. OF1-OF5

A Metabolic Axis of Immune Intractability.

Dominique C Hinshaw, Meet Patel, Lalita A Shevde.

Immune cells in the tumor niche robustly influence disease progression. Remarkably, in cancer, developmental pathways are reenacted. Many parallels between immune regulation of embryonic development and immune regulation of tumor progression can be drawn, with evidence clearly supporting an immune-suppressive microenvironment in both situations. In these ecosystems, metabolic and bioenergetic circuits guide and regulate immune cell differentiation, plasticity, and functional properties of suppressive and inflammatory immune subsets. As such, there is an emerging pattern of intersection across the dynamic process of ontogeny and the ever-evolving tumor neighborhood. In this article, we focus on the convergence of immune programming during ontogeny and in the tumor microenvironment. Exemplifying dysregulation of Hedgehog (Hh) activity, a key player during ontogeny, we highlight a critical convergence of these fields and the metabolic axis of the nutrient sensing hexosamine biosynthetic pathway (HBP) that integrates glucose, glutamine, amino acids, acetyl CoA, and uridine-5'-triphosphate (UTP), culminating in the synthesis of UDP-GlcNAc, a metabolite that functions as a metabolic and bioenergetic sensor. We discuss an emerging pattern of immune regulation, orchestrated by O-GlcNAcylation of key transcriptional regulators, spurring suppressive activity of dysfunctional immune cells in the tumor microenvironment.

DOI: https://doi.org/10.1158/2326-6066.CIR-23-0433
Nutrients. 2023 Dec 14. pii: 5104. [Epub ahead of print]15(24):

Oxidative Stress Induced by Chemotherapy: Evaluation of Glutathione and Its Related Antioxidant Enzyme Dynamics in Patients with Colorectal Cancer.

Feng-Fan Chiang, Shih-Chien Huang, Pei-Ting Yu, Te-Hsin Chao, Yi-Chia Huang.

  One of the mechanisms of chemotherapy is to increase the oxidative stress of cancer cells, leading to their apoptosis. Glutathione (GSH) and its related antioxidant enzymes might be stimulated to cope with increased oxidative stress during chemotherapy. Here, we studied the fluctuation in oxidative stress and GSH-related antioxidant capacities before tumor resection, after tumor resection, and after resection either with or without chemotherapy in patients with colorectal cancer (CRC). This was a cross-sectional and follow-up design. We followed patients before having tumor resection (pre-resection), one month after tumor resection (post-resection), and after the first scheduled chemotherapy (post-chemo). If patients were required to receive chemotherapy after tumor resection, they were assigned to the chemotherapy group. Eligible patients were scheduled to undergo six to twelve cycles of chemotherapy at 2-week intervals and received single, double, or triple chemotherapeutic drugs as required. Those patients who did not require chemotherapy were assigned to the non-chemotherapy group. Indicators of oxidative stress and GSH-related antioxidant capacities were determined at the above three time points. We found in 48 patients of the chemotherapy group and in 43 patients of the non-chemotherapy group different fluctuations in levels of oxidative stress indicators and GSH-related antioxidant capacities starting from pre-resection, post-resection through the post-chemo period. Both groups showed significantly or slightly increased levels of advanced oxidation protein products (AOPP), GSH, and its related enzymes in tumor tissues compared to adjacent normal tissues. Patients in the chemotherapy group had significantly lower plasma levels of GSH and glutathione disulfide (GSSG), but had significantly higher plasma glutathione peroxidase and glutathione reductase activities than patients in the non-chemotherapy group post-chemo. Plasma levels of malondialdehyde and AOPP were positively or negatively associated with GSH and GSSG levels post-chemo after adjustment for age, sex, and histological grading in patients receiving chemotherapy. These significant associations were, however, not seen in patients without chemotherapy. Patients with CRC may require higher GSH demands to cope with a greater oxidative stress resulting from chemotherapy.

Keywords:  antioxidant capacity; chemotherapy; colorectal cancer; glutathione; oxidative stress

DOI:  https://doi.org/10.3390/nu15245104