bims-glucam 2025-04-06 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–04–06
twelve papers selected by
Sreeparna Banerjee, Middle East Technical University

Targeting CXCR1 alleviates hyperoxia-induced lung injury through promoting glutamine metabolism.
HDAC6 and USP9X Control Glutamine Metabolism by Stabilizing GS to Promote Glioblastoma Tumorigenesis.
RNA‑seq analysis of predictive markers associated with glutamine metabolism in thyroid cancer.
The m6A reader IGF2BP2 promotes pancreatic cancer progression through the m6A-SLC1A5-mTORC1 axis.
MicroRNA-335 inhibits invasion and metastasis of prostate cancer by inhibiting glutamine metabolism pathway.
LOX-1 rewires glutamine ammonia metabolism to drive liver fibrosis.
l-[5-11C]Glutamine PET imaging noninvasively tracks dynamic responses of glutaminolysis in non-alcoholic steatohepatitis.
Role of metabolic transformation in cancer immunotherapy resistance: molecular mechanisms and therapeutic implications.
2-oxoglutarate triggers assembly of active dodecameric Methanosarcina mazei glutamine synthetase.
Unveiling the powerhouse: ASCL1-driven small cell lung cancer is characterized by higher numbers of mitochondria and enhanced oxidative phosphorylation.
Metabolic reprogramming of tumor microenviroment by engineered bacteria.
Development of a Single-Cell Spatial Metabolomics Method for the Characterization of Cell-Cell Metabolic Interactions.

Cell Rep. 2025 Apr 02. pii: S2211-1247(24)01354-8. [Epub ahead of print]44(4): 115003

Targeting CXCR1 alleviates hyperoxia-induced lung injury through promoting glutamine metabolism.

Hao Qin, Wei Zhuang, Xiucheng Liu, Junqi Wu, Shenghui Li, Yang Wang, Xiangming Liu, Chang Chen, Hao Zhang.

DOI: https://doi.org/10.1016/j.celrep.2024.115003
Adv Sci (Weinh). 2025 Mar 31. e2501553

HDAC6 and USP9X Control Glutamine Metabolism by Stabilizing GS to Promote Glioblastoma Tumorigenesis.

Go Woon Kim, Minhae Cha, Hien Thi My Ong, Jung Yoo, Yu Hyun Jeon, Sang Wu Lee, Soo Yeon Oh, Min-Jung Kang, Youngsoo Kim, So Hee Kwon.

  Glioblastoma (GBM) is the most common and the deadliest brain cancer. Glutamine anabolism mediated by glutamine synthetase (GS) is beneficial for GBM cell growth, especially under glutamine deprivation. However, the molecular mechanism underlying GS homeostasis in GBM remains undisclosed. Here, it is reported that histone deacetylase 6 (HDAC6) promotes GS deacetylation, stabilizing it via ubiquitin-mediated pathway. It is found that deubiquitination of GS is modulated by ubiquitin-specific peptidase 9, X-linked (USP9X). USP9X stabilizes GS by removing its K48-linked polyubiquitination on lysine 91 and 103. Accordingly, targeting HDAC6 and USP9X in vitro and in vivo represses GBM tumorigenesis by decreasing GS stability. Metabolic analysis shows that silencing HDAC6 and USP9X disrupts de novo nucleotide synthesis, thereby attenuating GBM cell growth. Furthermore, GS modulation by targeting HDAC6 and USP9X restrains the self-renewal capacity. These results suggest that HDAC6 and USP9X are crucial epigenetic enzymes that promote GBM tumorigenesis by modulating glutamine metabolism.

Keywords:  GS; HDAC6; USP9X; glioblastoma; glutamine metabolism

DOI:  https://doi.org/10.1002/advs.202501553
Mol Med Rep. 2025 Jun;pii: 145. [Epub ahead of print]31(6):

RNA‑seq analysis of predictive markers associated with glutamine metabolism in thyroid cancer.

Yi You, Yuheng Zhou, Zilu Chen, Longcheng Deng, Yaping Shen, Qin Wang, Wei Long, Yan Xiong, Foxing Tan, Haolin Du, Yan Yang, Jiang Zhong, Yunqian Ge, Youchen Li, Yan Huang.

  The incidence of thyroid cancer (TC) increases year by year. It is necessary to construct a prognostic model for risk stratification and management of TC patients. Glutamine metabolism is essential for tumor progression and the tumor microenvironment. The present study aimed to develop a predictive model for TC using a glutamine metabolism gene set. Differentially expressed genes in cells with high glutamine metabolism levels from single cell RNA‑sequencing data were compared with genes differentially expressed between normal and TC tissues from The Cancer Genome Atlas Program data. Through Boruta feature selection methods and multivariate Cox regression, six crucial genes were identified for a risk‑scoring system to develop a prognostic model. The role of each gene was verified in TC cells in vitro. A risk‑scoring system was developed according to the glutamine gene set to forecast the overall survival of TC patients. This risk score could stratify TC patients and minimize unnecessary surgeries and invasive treatments. In addition, signal induced proliferation associated 1 like 2 (SIPA1L2), an important gene in the prognostic model, knockdown in TPC‑1 and BCPAP cell lines enhanced TC cell proliferation, migration and invasion. A risk model was developed based on a glutamine metabolism gene set. The model has reference values for TC stratification.

Keywords:  Boruta; RNA‑seq; glutamine metabolism; multivariate Cox regression; thyroid cancer

DOI:  https://doi.org/10.3892/mmr.2025.13510
Cancer Cell Int. 2025 Mar 29. 25(1): 122

The m6A reader IGF2BP2 promotes pancreatic cancer progression through the m6A-SLC1A5-mTORC1 axis.

Xi Pu, Yuting Wu, Weiguo Long, Xinyu Sun, Xiao Yuan, Deqiang Wang, Xu Wang, Min Xu.

   BACKGROUND: Pancreatic cancer is a highly malignant digestive tumor. Glutamine metabolism is one of the important sources of tumors. N6-methyladenosine (m6A) modification plays a key role in regulating tumor metabolism and holds promise as a therapeutic target in various cancers, including pancreatic cancer. Disrupting m6A regulation of glutamine metabolism could impair tumor growth, offering potential new therapeutic strategies. However, the functional role of m6A modifications in pancreatic cancer, especially in glutamine metabolism, remains poorly understood.
METHODS: The Cancer Genome Atlas (TCGA) dataset and GEPIA bioinformatics tool were used to identify the relationship between m6A related proteins and the glutamine metabolism-associated genes, respectively. The biological effects of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) were investigated using in vitro and in vivo models. Methylated RNA immunoprecipitation sequencing (MeRIP-seq), MeRIP-PCR and RNA immunoprecipitation (RIP) were used to identify solute carrier family 1 member 5 (SLC1A5) as a direct target of IGF2BP2.
RESULTS: We found that IGF2BP2 expression and SLC1A5 were significantly correlated and both highly expressed in pancreatic cancer could predict poor prognosis in patients with pancreatic cancer. Functionally, silencing IGF2BP2 suppressed tumor growth and also inhibited glutamine uptake by tumor cells. Mechanistically, IGF2BP2 induced the m6A-SLC1A5-mTORC1 axis, facilitating the uptake of glutamine by pancreatic cancer cells and accelerate the progress of pancreatic cancer. Furthermore, silencing IGF2BP2 can enhance the sensitivity of pancreatic cancer to radiotherapy and chemotherapy.
CONCLUSION: Our findings suggest that IGF2BP2 promotes pancreatic cancer by activating the m6A-SLC1A5 -mTORC1 axis. Targeting the m6A machinery, particularly IGF2BP2, offers a novel therapeutic avenue for pancreatic cancer treatment. By disrupting the regulation of glutamine metabolism, we provide new insights into how m6A-based therapies could enhance the efficacy of current treatments and offer hope for improving patient outcomes in this difficult-to-treat cancer.

Keywords:  Glutamine metabolism; IGF2BP2; SLC1A5; Tumor treatment; m6A RNA modification

DOI:  https://doi.org/10.1186/s12935-025-03736-8
J Pharmacol Exp Ther. 2025 Mar;pii: S0022-3565(24)42179-4. [Epub ahead of print]392(3): 100530

MicroRNA-335 inhibits invasion and metastasis of prostate cancer by inhibiting glutamine metabolism pathway.

Ziqi Chen, Hekang Ding, Yunlong Zhu, Shuai Sun, Zhenyu Song, Li Zhang, Chaozhao Liang, Lingfan Xu.

  MicroRNAs play a crucial role in regulating tumor progression and invasion. Nevertheless, the expression of miRNA-335 in prostate cancer (PCa) and its clinical significance remain unelucidated. Here, we report that miRNA-335 functions as a tumor suppressor by regulating expression of glutaminase 1 (GLS1), a key enzyme of glutamine metabolism pathway, in PCa. In this study, we show that the expression of miRNA-335 is downregulated in PCa tissues. The level of miRNA-335 is even lower in highly invasive PCa cell lines. Furthermore, enhancing the expression of miRNA-335 inhibits PCa cell migration and invasion in vitro. Additionally, we identify GLS1 as the downstream effector, governed by miRNA-335 via 3'-untranslated region, and the direct regulation is verified by dual luciferase reporter assay. MiRNA-335 interrupts glutamine catabolism by inhibiting GLS1 enzymatic activity. Overexpression of miRNA-335 markedly suppresses tumor growth of PCa in vivo. To sum up, our results indicate that miRNA-335 acts as a tumor suppressor and has an important role in restraining the metastasis of PCa cells by targeting GLS1. These discoveries indicate that miRNA-335 could serve as a new prospective therapeutic target for PCa. SIGNIFICANCE STATEMENT: miRNA-335, a metabolism-related microRNA, is a potential therapeutic target for prostate cancer by interfering with glutaminase 1 activity.

Keywords:  Glutaminase 1; Glutamine; MicroRNA; MicroRNA-335; Prostate cancer; miRNA-335

DOI:  https://doi.org/10.1016/j.jpet.2024.100530
Mol Metab. 2025 Apr 01. pii: S2212-8778(25)00039-0. [Epub ahead of print] 102132

LOX-1 rewires glutamine ammonia metabolism to drive liver fibrosis.

Ruihua Huang, Hanyu Cui, Mohammed Abdulaziz Yahya Ali Alshami, Chuankui Fu, Wei Jiang, Mingyuan Cai, Shuhan Zhou, Xiaoyun Zhu, Changping Hu.

   OBJECTIVE: Liver fibrosis is a crucial condition for evaluating the prognosis of chronic liver disease. Lectin-1ike oxidized low density lipoprotein receptor-1 (LOX-1) has been shown potential research value and therapeutic targeting possibilities in different fibrotic diseases. However, the role of LOX-1 and the underlying mechanisms in liver fibrosis progression remain unclear.
METHODS: LOX-1 expression was detected in liver tissues from patients and rodents with liver fibrosis. LOX-1 knockout rats were subjected to CCl4 or methionine and choline-deficient diet (MCD) to induce liver fibrosis. Transcriptomic and metabolomics analysis were used to investigate the involvement and mechanism of LOX-1 on liver fibrosis.
RESULTS: We found that LOX-1 exacerbated liver fibrosis by promoting hepatic stellate cells (HSCs) activation. LOX-1 deletion reversed the development of liver fibrosis. We further verified that LOX-1 drove liver fibrosis by reprogramming glutamine metabolism through mediating isoform switching of glutaminase (GLS). Mechanistically, we revealed the crucial role of the LOX-1/OCT1/GLS1 axis in the pathogenesis of liver fibrosis. Moreover, LOX-1 rewired ammonia metabolism by regulating glutamine metabolism-urea cycle to drive the progression of liver fibrosis.
CONCLUSIONS: Our findings uncover the pivotal role of LOX-1 in the progression of liver fibrosis, enrich the pathological significance of LOX-1 regulation of hepatic ammonia metabolism, and provide an insight into promising targets for the therapeutic strategy of liver fibrosis, demonstrating the potential clinical value of targeting LOX-1 in antifibrotic therapy.

Keywords:  GLS; LOX-1; Liver fibrosis; Urea cycle

DOI:  https://doi.org/10.1016/j.molmet.2025.102132
Acta Pharm Sin B. 2025 Feb;15(2): 681-691

l-[5-11C]Glutamine PET imaging noninvasively tracks dynamic responses of glutaminolysis in non-alcoholic steatohepatitis.

Yiding Zhang, Lin Xie, Masayuki Fujinaga, Yusuke Kurihara, Masanao Ogawa, Katsushi Kumata, Wakana Mori, Tomomi Kokufuta, Nobuki Nengaki, Hidekatsu Wakizaka, Rui Luo, Feng Wang, Kuan Hu, Ming-Rong Zhang.

  Inhibiting glutamine metabolism has been proposed as a potential treatment strategy for improving non-alcoholic steatohepatitis (NASH). However, effective methods for assessing dynamic metabolic responses during interventions targeting glutaminolysis have not yet emerged. Here, we developed a positron emission tomography (PET) imaging platform using l-[5-11C]glutamine ([11C]Gln) and evaluated its efficacy in NASH mice undergoing metabolic therapy with bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES), a glutaminase 1 (GLS1) inhibitor that intervenes in the first and rate-limiting step of glutaminolysis. PET imaging with [11C]Gln effectively delineated the pharmacokinetics of l-glutamine, capturing its temporal-spatial pattern of action within the body. Furthermore, [11C]Gln PET imaging revealed a significant increase in hepatic uptake in methionine and choline deficient (MCD)-fed NASH mice, whereas systemic therapeutic interventions with BPTES reduced the hepatic avidity of [11C]Gln in MCD-fed mice. This reduction in [11C]Gln uptake correlated with a decrease in GLS1 burden and improvements in liver damage, indicating the efficacy of BPTES in mitigating NASH-related metabolic abnormalities. These results suggest that [11C]Gln PET imaging can serve as a noninvasive diagnostic platform for whole-body, real-time tracking of responses of glutaminolysis to GLS1 manipulation in NASH, and it may be a valuable tool for the clinical management of patients with NASH undergoing glutaminolysis-based metabolic therapy.

Keywords:  BPTES therapy; Glutaminase 1; Glutaminolysis; Metabolic intervention; Non-alcoholic steatohepatitis; Positron emission tomography; l-[5-11C]Glutamine

DOI:  https://doi.org/10.1016/j.apsb.2024.07.023
Discov Oncol. 2025 Apr 02. 16(1): 453

Role of metabolic transformation in cancer immunotherapy resistance: molecular mechanisms and therapeutic implications.

Sandesh Shende, Jaishriram Rathored, Tanushree Budhbaware.

   BACKGROUND: Immunotherapy in the treatment of cancer, with immune inhibitors helps in many cancer types. Many patients still encounter resistance to these treatments, though. This resistance is mediated by metabolic changes in the tumour microenvironment and cancer cells. The development of novel treatments to overcome resistance and boost immunotherapy's effectiveness depends on these metabolic changes.
OBJECTIVE: This review concentrates on the molecular mechanisms through which metabolic transformation contributes to cancer immunotherapy resistance. Additionally, research therapeutic approaches that target metabolic pathways to enhance immunotherapy for resistance.
METHODS: We used databases available on PubMed, Scopus, and Web of Science to perform a thorough review of peer-reviewed literature. focusing on the tumor microenvironment, immunotherapy resistance mechanisms, and cancer metabolism. The study of metabolic pathways covers oxidative phosphorylation, glycolysis, lipid metabolism, and amino acid metabolism.
RESULTS: An immunosuppressive tumour microenvironment is produced by metabolic changes in cancer cells, such as dysregulated lipid metabolism, enhanced glutaminolysis, and increased glycolysis (Warburg effect). Myeloid-derived suppressor cells and regulatory T cells are promoted, immune responses are suppressed, and T cell activity is impaired when lactate and other metabolites build up. changes in the metabolism of amino acids in the pathways for arginine and tryptophan, which are nutrients crucial for immune function. By enhancing their function in the tumour microenvironment, these metabolic alterations aid in resistance to immune checkpoint inhibitors.
CONCLUSION: Metabolic change plays a key role in cancer immunotherapy resistance. Gaining knowledge of metabolic processes can help develop efficient treatments that improve immunotherapy's effectiveness. In order to determine the best targets for therapeutic intervention, future studies should concentrate on patient-specific metabolic profiling.

Keywords:  Amino acid metabolism; Cancer metabolism; Glycolysis; Immune checkpoint inhibitors; Immunotherapy resistance; Tumour microenvironment

DOI:  https://doi.org/10.1007/s12672-025-02238-3
Elife. 2025 Mar 31. pii: RP97484. [Epub ahead of print]13

2-oxoglutarate triggers assembly of active dodecameric Methanosarcina mazei glutamine synthetase.

Eva Herdering, Tristan Reif-Trauttmansdorff, Anuj Kumar, Tim Habenicht, Georg Hochberg, Stefan Bohn, Jan Schuller, Ruth Anne Schmitz.

  Glutamine synthetases (GS) are central enzymes essential for the nitrogen metabolism across all domains of life. Consequently, they have been extensively studied for more than half a century. Based on the ATP-dependent ammonium assimilation generating glutamine, GS expression and activity are strictly regulated in all organisms. In the methanogenic archaeon Methanosarcina mazei, it has been shown that the metabolite 2-oxoglutarate (2-OG) directly induces the GS activity. Besides, modulation of the activity by interaction with small proteins (GlnK1 and sP26) has been reported. Here, we show that the strong activation of M. mazei GS (GlnA1) by 2-OG is based on the 2-OG dependent dodecamer assembly of GlnA1 by using mass photometry (MP) and single particle cryo-electron microscopy (cryo-EM) analysis of purified strep-tagged GlnA1. The dodecamer assembly from dimers occurred without any detectable intermediate oligomeric state and was not affected in the presence of GlnK1. The 2.39 Å cryo-EM structure of the dodecameric complex in the presence of 12.5 mM 2-OG demonstrated that 2-OG is binding between two monomers. Thereby, 2-OG appears to induce the dodecameric assembly in a cooperative way. Furthermore, the active site is primed by an allosteric interaction cascade caused by 2-OG-binding towards an adaption of an open active state conformation. In the presence of additional glutamine, strong feedback inhibition of GS activity was observed. Since glutamine dependent disassembly of the dodecamer was excluded by MP, feedback inhibition most likely relies on the binding of glutamine to the catalytic site. Based on our findings, we propose that under nitrogen limitation the induction of M. mazei GS into a catalytically active dodecamer is not affected by GlnK1 and crucially depends on the presence of 2-OG.

Keywords:  2-oxoglutarate; Methanosarcina mazei; archaea; biochemistry; chemical biology; glutamine synthetase; infectious disease; microbiology; nitrogen metabolism; regulation

DOI:  https://doi.org/10.7554/eLife.97484
Cancer Metab. 2025 Mar 31. 13(1): 16

Unveiling the powerhouse: ASCL1-driven small cell lung cancer is characterized by higher numbers of mitochondria and enhanced oxidative phosphorylation.

Anna Solta, Büsra Ernhofer, Kristiina Boettiger, Christian Lang, Zsolt Megyesfalvi, Theresa Mendrina, Dominik Kirchhofer, Gerald Timelthaler, Beata Szeitz, Melinda Rezeli, Clemens Aigner, Arvand Haschemi, Lukas W Unger, Balazs Dome, Karin Schelch.

   BACKGROUND: Small cell lung cancer (SCLC) is an aggressive malignancy with distinct molecular subtypes defined by transcription factors and inflammatory characteristics. This follow-up study aimed to validate the unique metabolic phenotype in achaete-scute homologue 1 (ASCL1)-driven SCLC cell lines and human tumor tissue.
METHODS: Metabolic alterations were analyzed using proteomic data. Structural and functional differences of mitochondria were investigated using qPCR, flow cytometry, confocal imaging, and transmission electron microscopy and seahorse assays. Several metabolic inhibitors were tested using MTT-based and clonogenic assays. Single-cell enzyme activity assays were conducted on cell lines and tumor tissue samples of SCLC patients.
RESULTS: We found increased mitochondrial numbers correlating with higher oxidative phosphorylation activity in ASCL1-dominant cells compared to other SCLC subtypes. Metabolic inhibitors targeting mitochondrial respiratory complex-I or carnitine palmitoyltransferase 1 revealed higher responsiveness in SCLC-A. Conversely, we demonstrated that non-ASCL1-driven SCLCs with lower oxidative signatures show dependence on glutaminolysis as evidenced by the enhanced susceptibility to glutaminase inhibition. Accordingly, we detected increased glutamate-dehydrogenase activity in non-ASCL1-dominant cell lines as well as in human SCLC tissue samples.
CONCLUSIONS: Distinct SCLC subtypes exhibit unique metabolic vulnerabilities, suggesting potential for subtype-specific therapies targeting the respiratory chain, fatty acid transport, or glutaminolysis.

Keywords:  Metabolism; Molecular subtypes; Oxidative phosphorylation; Small cell lung cancer

DOI:  https://doi.org/10.1186/s40170-025-00382-6
Semin Cancer Biol. 2025 Mar 27. pii: S1044-579X(25)00049-5. [Epub ahead of print]112 58-70

Metabolic reprogramming of tumor microenviroment by engineered bacteria.

Heng Wang, Fang Xu, Chao Wang.

  The tumor microenvironment (TME) is a complex ecosystem that plays a crucial role in tumor progression and response to therapy. The metabolic characteristics of the TME are fundamental to its function, influencing not only cancer cell proliferation and survival but also the behavior of immune cells within the tumor. Metabolic reprogramming-where cancer cells adapt their metabolic pathways to support rapid growth and immune evasion-has emerged as a key factor in cancer immunotherapy. Recently, the potential of engineered bacteria in cancer immunotherapy has gained increasing recognition, offering a novel strategy to modulate TME metabolism and enhance antitumor immunity. This review summarizes the metabolic properties and adaptations of tumor and immune cells within the TME and summarizes the strategies by which engineered bacteria regulate tumor metabolism. We discuss how engineered bacteria can overcome the immunosuppressive TME by reprogramming its metabolism to improve antitumor therapy. Furthermore, we examine the advantages, potential challenges, and future clinical translation of engineered bacteria in reshaping TME metabolism.

Keywords:  Engineered bacteria; Immunotherapy; Metabolic reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.semcancer.2025.03.003
Anal Chem. 2025 Apr 04.

Development of a Single-Cell Spatial Metabolomics Method for the Characterization of Cell-Cell Metabolic Interactions.

Yaqi Zhang, Panpan Chen, Haoyuan Geng, Min Li, Shiping Chen, Bangzhen Ma, Yan Ma, Jianjun Lai, Xiaoqing Cui, Wei Chong, Hao Chen, Xiao Wang, Chenglong Sun.

Tumor microenvironment (TME) is characterized by complex cellular composition and high molecular heterogeneity. Characterizing the metabolic interactions between different cells in the TME is important for understanding the molecular signatures of tumors and identifying potential metabolic vulnerabilities for tumor treatment. In this research, we develop a single-cell spatial metabolomics method to profile cell-specific metabolic signatures and cell-cell metabolic interactions using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). Different low-molecular-weight metabolites and lipids including glutamate, aspartate, glutamine, taurine, phenylalanine, glutathione, fatty acids, phospholipids, etc. were successfully detected and imaged after optimizing cell culture conductive slides, cell washing, and fixation procedures. Subsequently, we carried out single-cell spatial metabolomics on H460 large-cell lung cancer cells, HT-29 colorectal cancer cells, A549 lung cancer cells, HUH-7 liver cancer cells, and cancer-fibroblasts coculture system. We revealed that the metabolic profiles of both cancer cells and fibroblasts were altered after cell coculture. Glutamate and aspartate significantly increased in fibroblasts after coculture with cancer cells, corresponding to their indispensable roles in the creation of pro-cancer microenvironment. In addition, we discovered that the expressions of fatty acids and phospholipids in tumor cells and fibroblasts were also changed after cell coculture, which is closely related to the competition for energy and nutrient metabolites between different cells. We anticipate this single-cell analysis method to be broadly used in the investigations of diverse cellular models and cell-cell metabolic interactions.

DOI: https://doi.org/10.1021/acs.analchem.5c00384