bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2025–06–15
twelve papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. Lifting the veil on tumor metabolism: A GDH1-focused perspective.
  2. siRNA micelleplexes-mediated glutamine metabolism re-engineering for vascular normalization-boosted photo-immunotherapy.
  3. Epigenetic roles of lysine-specific demethylase 1 (LSD1) in cancer metabolism.
  4. The Metabolic Orchestration of Immune Evasion in Glioblastoma: From Molecular Perspectives to Therapeutic Vulnerabilities.
  5. Unveiling the Maze: Branched-Chain Amino Acids Fueling the Dynamics of Cancer Metabolism and Progression.
  6. Metabolic reprogramming by PRDM16 drives cytarabine resistance in acute myeloid leukemia.
  7. Glutamine Attenuates Inflammation and Oxidative Stress in Ulcerative Colitis by Suppressing Wilms' Tumor 1 Associated Protein-Mediated N6-Methyladenosine Modification of Nuclear Receptor Coactivator 3.
  8. Arsenite-Mediated Transcriptional Regulation of Glutathione Synthesis in Mammalian Primary Cortical Astrocytes.
  9. Transglutaminase 2-mediated glutamine deamidation enhances p21 stability during senescence.
  10. Myeloid Glutamine Synthetase Protects Against Acute Liver Injury in Mice Independent of Its Enzyme Activity.
  11. OGDHL regulates nucleotide metabolism, tumor growth, and neuroendocrine marker expression in prostate cancer.
  12. An Overview of Oligodendrocyte Metabolism.
  1. iScience. 2025 Jun 20. 28(6): 112551
    Lifting the veil on tumor metabolism: A GDH1-focused perspective.
    Sisi Zhou, Huaer Wu, Yun Chen, Jiawei Lv, Shufang Chen, Hua Yu, Tiezhu Shi, Xiongjun Wang, Lingyun Xiao.
      Tumors depend on glutamine for energy production, biosynthesis, and redox homeostasis. Glutamate dehydrogenase 1 (GDH1) primarily catalyzes the oxidative deamination of glutamate to α-ketoglutarate (α-KG) and ammonia, utilizing NAD+ or NADP+ as cofactors. α-KG is a tricarboxylic acid (TCA) cycle intermediate at the nexus of multiple metabolic pathways, fueling the TCA cycle for energy production or providing intermediates essential for lipid, amino acid, and nucleotide synthesis. Its derivatives, succinate and fumarate, function as oncometabolites that promote tumor progression through diverse mechanisms. Additionally, α-KG is an essential cofactor for α-KG-dependent dioxygenases (2-OGDDs), regulating epigenetic modifications that drive tumorigenesis. GDH1 may also catalyze the reductive amination of α-KG to glutamate under glutamine deprivation or hypoxic conditions. The roles of GDH1 in tumors are context-dependent, influencing progression through metabolic and epigenetic mechanisms. This review discusses GDH1's multifaceted functions and advances in targeting it for cancer therapy.
    Keywords:  Cancer
    DOI:  https://doi.org/10.1016/j.isci.2025.112551
  2. Acta Pharm Sin B. 2025 Apr;15(4): 2237-2252
    siRNA micelleplexes-mediated glutamine metabolism re-engineering for vascular normalization-boosted photo-immunotherapy.
    Yunfei Yi, Zhangwen Peng, Yuanqi Liu, Huisong Hao, Liu Yu, Simin Wen, Shengjie Sun, Jianlin Shi, Meiying Wu, Lin Mei.
      Among tumor microenvironment (TME), the entire metabolic characteristics of tumor-resident cells are reprogrammed to benefit the expansion of tumor cells, which count on glutamine in large part to fuel the tricarboxylic acid cycle for energy generation and anabolic metabolism support. Endothelial cells that are abducted by tumor cells to form a pathological tumor vascular network for constructing the hypoxic immunosuppressive TME, also rely on glutaminolysis as the "engine" of angiogenesis. Additionally, the glutamine metabolic preference benefits the polarization of TAMs towards pro-tumoral M2 phenotype as well. Herein, we developed a type of siRNA micelleplexes (MH@siGLS1) to reverse immunosuppressive TME by targeting glutaminolysis within tumor-resident cells for tumor vasculature normalization- and TAMs repolarization-enhanced photo-immunotherapy. Tumor cell starvation and antioxidant system destruction achieved by MH@siGLS1-mediated glutaminolysis inhibition could promote photodynamic therapy efficacy, which was available to trigger immunogenic cell death for adaptive antitumor immune responses. Meanwhile, glutaminolysis inhibition of tumor endothelial cells and TAMs could realize tumor vascular normalization and TAMs repolarization for antitumor immunity amplification. This study provides a unique perspective on cancer treatments by focusing on the interrelations of metabolic characteristics and the biofunctions of various cell types within TME.
    Keywords:  Glutaminase 1; Glutaminolysis inhibition; Immunogenic cell death; Immunosuppressive tumor microenvironment; Photo-immunotherapy; Photodynamic therapy; TAM repolarization; Tumor vascular normalization
    DOI:  https://doi.org/10.1016/j.apsb.2025.02.020
  3. Drug Discov Today. 2025 Jun 08. pii: S1359-6446(25)00110-2. [Epub ahead of print] 104397
    Epigenetic roles of lysine-specific demethylase 1 (LSD1) in cancer metabolism.
    Bing Cheng, Xiangyu Xu, Boyi Fan, Ting Ma, Bin Yu.
      Lysine-specific demethylase 1 (LSD1) is a histone demethylase with a crucial role in cancer initiation and progression. Several LSD1 inhibitors and degraders are undergoing clinical trials. Metabolic reprogramming, a key hallmark of cancer cells, allows them to survive in harsh environments. Studies have highlighted the roles of epigenetic regulators, particularly LSD1, in modulating metabolic pathways to promote cancer cell growth, metastasis, and invasion. In this review, we highlight the roles of glucose, glutamine (Gln), and fatty acid (FA) metabolism in tumor cells, as well as the signaling pathways through which LSD1 regulates these metabolic processes, aiming to provide new insights and strategies for cancer treatment.
    Keywords:  LSD1; cancer metabolism; cancer therapy; epigenetics; metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.drudis.2025.104397
  4. Cancers (Basel). 2025 Jun 04. pii: 1881. [Epub ahead of print]17(11):
    The Metabolic Orchestration of Immune Evasion in Glioblastoma: From Molecular Perspectives to Therapeutic Vulnerabilities.
    Ravi Medikonda, Matthew Abikenari, Ethan Schonfeld, Michael Lim.
      Glioblastoma (GBM) is a highly aggressive primary brain cancer with dismal prognoses despite current standards of care. Immunotherapy is being explored for GBM, given its promising results in other solid malignancies; however, the results from early clinical studies in GBM are disappointing. It has been discovered that GBM has numerous mechanisms of immune resistance, including the physical blood-brain barrier, high intratumoral and intertumoral heterogeneity, and numerous cellular and molecular components in the tumor microenvironment (TME) that promote immunosuppression. Furthermore, GBM utilizes numerous metabolic pathways to establish a survival advantage in the TME. Recently, it has begun to become evident that these complex metabolic pathways that promote GBM growth and invasion also contribute to tumor immune resistance. Aerobic glycolysis provides tumor cells with ample ATP while depleting key glucose and increasing acidity in the TME. Increased glutamine, tryptophan, and arginine metabolism deprives T cells of these necessary amino acids for proper anti-tumor function. Sphingolipid metabolism promotes an immunosuppressive phenotype in the TME and affects immune cell trafficking. This review will discuss, in detail, the key metabolic pathways relevant to GBM pathophysiology which also modulate host immunosuppression.
    Keywords:  arginine depletion; glioblastoma; immune evasion; immunometabolism; sphingolipid pathways; tryptophan metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers17111881
  5. Cancers (Basel). 2025 May 23. pii: 1751. [Epub ahead of print]17(11):
    Unveiling the Maze: Branched-Chain Amino Acids Fueling the Dynamics of Cancer Metabolism and Progression.
    Kai Xu, Pratham Shah, Dhruvi Makhanasa, Md Wasim Khan.
      Branched-chain amino acids (BCAAs) are essential for protein synthesis and play a crucial role in activating signaling pathways that regulate cell growth and division. Growing evidence reveals their complex role in cancer, particularly in how they support the metabolic reprogramming of tumor cells. BCAAs contribute to an environment that promotes tumor growth and survival by affecting energy balance and key cellular signaling networks. This review highlights recent advances in understanding how BCAAs influence cancer metabolism, emphasizing their dual function as both essential nutrients and sources of metabolic fuel. It also explores how BCAAs interact with other metabolic pathways, revealing potential targets for therapy. By uncovering these cancer-specific dependencies on BCAAs, this work points to promising strategies for disrupting tumor progression and developing new treatment approaches.
    Keywords:  BCAAs; cancer metabolism; metabolic reprogramming
    DOI:  https://doi.org/10.3390/cancers17111751
  6. Haematologica. 2025 Jun 12. 0
    Metabolic reprogramming by PRDM16 drives cytarabine resistance in acute myeloid leukemia.
    Junji Ikeda, Hiroyoshi Kunimoto, Yusuke Saito, Shin-Ichi Tsujimoto, Masanobu Takeuchi, Ayaka Miura, Takayuki Kurosawa, Koichi Murakami, Ikuma Kato, Megumi Funakoshi-Tago, Akihiko Yokoyama, Norio Shiba, Souichi Adachi, Daisuke Tomizawa, Tomohiko Tamura, Shuichi Ito, Hideaki Nakajima.
      Acute myeloid leukemia (AML) patients with high PRDM16 expression frequently experience induction failure and have a poor prognosis. However, the molecular mechanisms underlying these clinical features remain elusive. We found that murine AML cells transformed by MLL::AF9 fusion and oncogenic short-isoform Prdm16 overexpression (hereafter, MF9/sPrdm16) exhibited resistance to cytarabine (AraC), but not to anthracycline, both in vitro and in vivo. Intriguingly, MF9/sPrdm16 cells displayed a gene expression signature of high oxidative phosphorylation (OxPHOS) and increased mitochondrial respiration. The inhibition of mitochondrial respiration with metformin or tigecycline abrogated AraC resistance in MF9/sPrdm16 cells via an energetic shift toward low OxPHOS status. Furthermore, sPrdm16 upregulated Myc and the glutamine transporter Slc1a5, activating TCA cycle and glutaminolysis. Of note, both OxPHOS and MYC-target gene signatures were significantly enriched in AML patient samples with high PRDM16 expression. Together, we showed that PRDM16 overexpression activates mitochondrial respiration through metabolic reprogramming via MYC-SLC1A5-Glutaminolysis axis, thereby conferring AraC resistance on AML cells. These results suggest that targeting mitochondrial respiration might be a novel treatment strategy to overcome chemoresistance in AML patients with high PRDM16 expression.
    DOI:  https://doi.org/10.3324/haematol.2024.287265
  7. Chem Biol Drug Des. 2025 Jun;105(6): e70110
    Glutamine Attenuates Inflammation and Oxidative Stress in Ulcerative Colitis by Suppressing Wilms' Tumor 1 Associated Protein-Mediated N6-Methyladenosine Modification of Nuclear Receptor Coactivator 3.
    Liangxian Jiang, Shuai Liu, Feifei Ye, Xiaowei Yu.
      Ulcerative colitis (UC) is a chronic inflammatory condition. Glutamine (Gln) has shown an improved effect on UC. However, its molecular determinants are incompletely understood. NCM460 cells were stimulated with lipopolysaccharide (LPS) to generate an in vitro UC cell model, and dextran sulfate sodium (DSS)-induced UC models were established in mice. Methylated RNA immunoprecipitation (MeRIP) and messenger RNA (mRNA) stability experiments were used to validate the influence of Wilms' tumor 1-associating protein (WTAP) on nuclear receptor coactivator-3 (NCOA3) mRNA. In LPS-exposed NCM460 cells, Gln promoted NCOA3 expression and reduced WTAP expression. Gln relieved LPS-triggered inflammation, oxidative stress, and apoptosis in NCM460 cells, which were abolished by NCOA3 downregulation or WTAP upregulation. Mechanistically, Gln suppressed WTAP-mediated m6A modification of NCOA3 mRNA. WTAP reduction attenuated LPS-evoked NCM460 cell phenotype alterations, which were reversed by NCOA3 downregulation. Furthermore, Gln reduced the DAI score and histopathological changes, increased colon length, and attenuated inflammation and oxidative stress in DSS-induced UC mice, which were abrogated by WTAP increase. We showed that the WTAP/NCOA3 axis underlies the protective effect of Gln on UC, providing a rationale for Gln as a promising anti-UC agent.
    Keywords:  NCOA3; WTAP; glutamine; m6A modification; ulcerative colitis
    DOI:  https://doi.org/10.1111/cbdd.70110
  8. Int J Mol Sci. 2025 Jun 04. pii: 5375. [Epub ahead of print]26(11):
    Arsenite-Mediated Transcriptional Regulation of Glutathione Synthesis in Mammalian Primary Cortical Astrocytes.
    Jacob P Leisawitz, Jiali He, Caroline Baggeroer, Sandra J Hewett.
      Arsenic, a potent metalloid contaminant of drinking water, is known for its ability to act as an initiator and modulator of disease in a variety of human tissues. Upon ingestion, arsenic is bio-transformed in the liver into a variety of metabolites, including arsenite. Arsenite permeates the blood-brain barrier (BBB), inducing oxidative stress that can be detrimental to brain neurons. As the primary glial cell at the BBB interface, astrocytes play a pivotal role in detoxifying xenobiotics such as arsenite via the production of the tripeptide antioxidant γ-glutamylcysteine, or glutathione (GSH). In this study, we assessed the mRNA levels of key components of the GSH synthetic pathway in astrocytes exposed to arsenite compared to vehicle controls. These components included xCT [substrate-specific light chain of the substrate importing transporter, system xc- (Sxc-)], glutamate-cysteine ligase [both catalytic (GCLC) and modifying (GCLM) subunits], and glutathione synthetase (GS). Additionally, we analyzed protein levels of some components by Western blotting and evaluated functional activity of Sxc- using a fluorescence-based cystine uptake assay. Finally, we utilized a luminescence-based glutathione assay to determine the intracellular and extracellular GSH content in arsenite-treated cells. Arsenite significantly increased xCT, GCLC, GCLM, and GS mRNA levels, an effect blocked by the transcriptional inhibitor actinomycin D (ActD). A corresponding increase in Sxc- activity was also observed in the arsenite treatment groups, along with significant increases in GCLC and GCLM protein expression. However, no increase in GS protein expression was detected. Finally, arsenite treatment significantly increased extracellular GSH levels, an effect which was also prevented by the inclusion of ActD. Overall, our study provides evidence that arsenite transcriptionally regulates several cellular processes necessary for GSH synthesis in primary cortical astrocyte cultures, thereby contributing to a better understanding of how this environmental toxicant influences antioxidant defenses in the brain. However, these results should be interpreted with caution regarding their applicability to vivo systems.
    Keywords:  RNA; amino acid transport systems; arsenicals; astrocytes; blood–brain barrier; genetic; glutathione; glutathione synthetase; glutathione-cysteine ligase; messenger; oxidative stress; transcription
    DOI:  https://doi.org/10.3390/ijms26115375
  9. Proc Natl Acad Sci U S A. 2025 Jun 17. 122(24): e2419762122
    Transglutaminase 2-mediated glutamine deamidation enhances p21 stability during senescence.
    Yi-Wen Liao, Hsi-Hsien Hsieh, Jin-Wei Yeh, Hsin-Chiao Wang, Shang-Yi Huang, Pei-Yu Wang, Jing-Jer Lin.
      The limited doubling capacity of human cells, known as replicative senescence or cellular senescence, is a major factor in cellular aging. This process is triggered by telomere erosion, which activates a p53-mediated DNA damage response (DDR) that halts cell proliferation. p53, a transcriptional regulator, responds to DNA damage by increasing the expression of the cyclin-dependent kinase inhibitor p21. p21 then arrests cells at specific stages of the cell cycle. Additionally, p53 upregulates serpinB2 (also known as plasminogen activator inhibitor-2, PAI-2), which stabilizes p21 in senescent cells. This study reveals that serpinB2 upregulation activates transglutaminase 2 (TGM2), which selectively deamidates multiple glutamine residues on p21, stabilizing the protein and halting cell proliferation in senescent cells. Moreover, inhibiting TGM2-mediated deamidation accelerates p21 degradation, delaying the onset of senescence. Notably, pharmacological inhibition of TGM2 improves aging phenotypes in an accelerated aging model of chronic kidney disease (CKD). These findings provide crucial insights into the role of TGM2-mediated enzymatic deamidation in senescence and its potential relevance to age-associated conditions.
    Keywords:  TGM2; p21; senescence; serpinB2
    DOI:  https://doi.org/10.1073/pnas.2419762122
  10. Liver Int. 2025 Jul;45(7): e70105
    Myeloid Glutamine Synthetase Protects Against Acute Liver Injury in Mice Independent of Its Enzyme Activity.
    Jianghong Yu, Menglin Shi, Yumeng Guo, Kaiyi Fu, Jun Zhang, Hao Ding, Mengxiao Ge, Shuangyi Sun, Huilu Zhang, Jie Liu.
       BACKGROUND: Glutamine synthetase (GS, encoded by Glul) is a well-known ammonia-detoxifying enzyme, but its function in acute liver injury (ALI) remains unclear.
    METHODS: Lipopolysaccharide (LPS) and D-galactosamine (D-GalN) were utilised to construct the murine ALI model. C57BL/6J-Glulem1(flox)Smoc mice (Glulf/f) and B6.129-Lyz2tm1(cre)smoc (Lyz2-Cre) transgenic mice were crossed to generate Lyz2+Glulf/f (Glul∆Lyz2) mice with a selectively knockout of Glul in myeloid cells. Histological staining experiments were performed to evaluate liver injury. Flow cytometry and RNA sequencing analyses were conducted to investigate the effects of Glul deficiency on liver immunity. Additionally, several strategies were applied to intervene ALI in mice, including administration of CCL2 neutralising antibody or GS inhibitor L-methionine sulfoximine (MSO), as well as adeno-associated virus (AAV)-mediated enhancement of GS expression.
    RESULTS: The expression of Glul in myeloid cells was downregulated in wild-type mice after ALI modelling by LPS/D-GalN. Moreover, Glul∆Lyz2 mice demonstrated aggravated ALI and higher mortality upon LPS/D-GalN challenge, compared to the control Glulf/f littermates. Notably, Glul deficiency significantly contributed to the activation of monocyte-derived macrophages (MoMFs), secretion of C-C chemokine ligand 2 (CCL2) and the recruitment of C-C chemokine receptor 2-positive monocytes. Treatment with CCL2 neutralising antibody significantly alleviated ALI by inhibiting MoMF activation. Interestingly, although MSO treatment effectively blocked the enzyme activity of GS, it exerted both preventive and therapeutic effects against ALI, which could be attributed to the elevation of GS protein level. Therefore, in vivo global or myeloid GS was overexpressed via AAV delivery system, which demonstrated potent protective efficacy against ALI.
    CONCLUSIONS: This study provided an updated look at the protective role of GS independent of its enzyme activity in ALI and shed light on the potential therapeutical strategies for ALI intervention.
    Keywords:  C‐C chemokine ligand 2; acute liver injury; glutamine synthetase; monocyte‐derived macrophages
    DOI:  https://doi.org/10.1111/liv.70105
  11. bioRxiv. 2025 Jun 01. pii: 2025.05.28.656673. [Epub ahead of print]
    OGDHL regulates nucleotide metabolism, tumor growth, and neuroendocrine marker expression in prostate cancer.
    Matthew J Bernard, Angel Ruiz, Johnny A Diaz, Nicholas M Nunley, Rachel N Dove, Kylie Y Heering, Sachi Bopardikar, Andrea Gallardo, Takao Hashimoto, Raag Agrawal, Chad M Smith, Blake R Wilde, Nedas Matulionis, Helen M Richards, Marina N Sharifi, Joshua M Lang, Shuang G Zhao, Michael C Haffner, Paul C Boutros, Heather R Christofk, Andrew S Goldstein.
      Cells regularly adapt their metabolism in response to changes in their microenvironment or biosynthetic needs. Prostate cancer cells leverage this metabolic plasticity to evade therapies targeting the androgen receptor (AR) signaling pathway. For example, nucleotide metabolism plays a critical role in treatment-resistant prostate cancer by supporting DNA replication, DNA damage response and cell fate decisions. Identifying novel regulators of nucleotide metabolism in treatment-resistant cancer that are dispensable for the health of normal cells may lead to new therapeutic approaches less toxic than commonly used chemotherapies targeting nucleotide metabolism. We identify the metabolic enzyme Oxoglutarate Dehydrogenase-Like (OGDHL), named for its structural similarity to the tricarboxylic acid (TCA) cycle enzyme Oxoglutarate Dehydrogenase (OGDH), as a regulator of nucleotide metabolism, tumor growth, and treatment-induced plasticity in prostate cancer. While OGDHL is a tumor-suppressor in various cancers, we find that its loss impairs prostate cancer cell proliferation and tumor formation while having minimal impact on TCA cycle activity. Loss of OGDHL profoundly decreases nucleotide metabolite pools, induces the DNA damage response marker Ɣ2AX, and alters androgen receptor inhibition-induced plasticity, including suppressing the neuroendocrine markers DLL3 and HES6. Finally, OGDHL is highly expressed in neuroendocrine prostate cancer (NEPC). These findings support an unexpected role of OGDHL in prostate cancer, where it functions to sustain nucleotide pools for proliferation, DNA repair, and AR inhibition-induced plasticity.
    DOI:  https://doi.org/10.1101/2025.05.28.656673
  12. Adv Neurobiol. 2025 ;43 155-179
    An Overview of Oligodendrocyte Metabolism.
    Qi Han, Jin Cheng.
      Oligodendrocytes (OLs) exhibit complex metabolic interactions essential for neuronal function and CNS health. This chapter analyzes the metabolism of OLs, particularly glucose, lipid, and amino acid metabolism, and their impact on myelin synthesis, maintenance, and CNS resilience. OLs utilize glucose for energy through glycolysis and the pentose phosphate pathway, supporting ATP production and antioxidative defenses. Lipid synthesis, including cholesterol and sphingolipid production, is critical for maintaining myelin integrity and rapid signal conduction. Furthermore, amino acid pathways, such as those involving glutamine and serine, modulate OL differentiation and remyelination. OLs also provide metabolic support to neurons through lactate shuttling and their interactions with astrocytes in the Panglial network, ensuring sustained energy flow. Dysregulation of OL metabolic functions underlies demyelinating diseases, such as multiple sclerosis, neurodegenerative disorders, and neuropsychiatric conditions, highlighting the therapeutic potential of targeting OL metabolism to enhance remyelination and neuroprotection.
    Keywords:  Amino acid metabolism; Glucose metabolism; Glutamate-glutamine cycle; Lactate shuttle; Lipid metabolism; Metabolic interaction; Myelin synthesis
    DOI:  https://doi.org/10.1007/978-3-031-87919-7_7
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