bims-glucam 2025-06-08 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–06–08
ten papers selected by
Sreeparna Banerjee, Middle East Technical University

Pathway metabolite ratios reveal distinctive glutamine metabolism in a subset of proliferating cells.
Mechanism of SLC1A5 Regulation of Glutamine Metabolism to Promote Ferroptosis Sensitivity in Endometriosis.
Targeting c-MYC has a Key Role in Hepatocellular Carcinoma Therapy.
2D versus 3D tumor-on-chip models to study the impact of tumor organization on metabolic patterns in vitro.
Metabolic reprogramming and therapeutic targeting in non-small cell lung cancer: emerging insights beyond the Warburg effect.
Sustained Glucose Turnover Flux Distinguishes Cancer Cachexia from Nutrient Limitation.
Cancer stem cells amino acid metabolism: Roles, mechanisms, and intervention strategies.
Glutamate promotes triple-negative breast cancer development through IRE1α/XBP1-mediated macrophage polarization: mechanism insights and therapy.
Combining old with new: A novel approach to studying human brain metabolism.
Single-cell and bulk transcriptome analyses reveal elevated amino acid metabolism promoting tumor-directed immune evasion in colorectal cancer.

Mol Syst Biol. 2025 Jun 05.

Pathway metabolite ratios reveal distinctive glutamine metabolism in a subset of proliferating cells.

Nancy T Santiappillai, Yue Cao, Mariam F Hakeem-Sanni, Jean Yang, Lake-Ee Quek, Andrew J Hoy.

  Large-scale metabolomic analyses of pan-cancer cell line panels have provided significant insights into the relationships between metabolism and cancer cell biology. Here, we took a pathway-centric approach by transforming targeted metabolomic data into ratios to study associations between reactant and product metabolites in a panel of cancer and non-cancer cell lines. We identified five clusters of cells from various tissue origins. Of these, cells in Cluster 4 had high ratios of TCA cycle metabolites relative to pyruvate, produced more lactate yet consumed less glucose and glutamine, and greater OXPHOS activity compared to Cluster 3 cells with low TCA cycle metabolite ratios. This was due to more glutamine cataplerotic efflux and not glycolysis in cells of Cluster 4. In silico analyses of loss-of-function and drug sensitivity screens showed that Cluster 4 cells were more susceptible to gene deletion and drug targeting of glutamine metabolism and OXPHOS than cells in Cluster 3. Our results highlight the potential of pathway-centric approaches to reveal new aspects of cellular metabolism from metabolomic data.

Keywords:  Cancer Cell Lines; Glucose Metabolism; Glutamine Metabolism; Metabolic Pathways; Metabolomics

DOI:  https://doi.org/10.1038/s44320-025-00099-0
Front Biosci (Landmark Ed). 2025 May 21. 30(5): 36781

Mechanism of SLC1A5 Regulation of Glutamine Metabolism to Promote Ferroptosis Sensitivity in Endometriosis.

Hui-Yu Ma, Huan-Yu Wu, Yu-Ting Xiang, Yu-Yin Liu, Jin Xie, Peng-Yu Cai, Bin Zhang, Yu-Hang Zhang, Ming-Xiu Wu.

   BACKGROUND: Endometriosis (EMs) is a chronic gynecological disorder associated with ectopic endometrial tissue, inflammation, oxidative stress, and mitochondrial dysfunction. A promising strategy for treating EMs is to target ferroptosis, a programmed cell death mechanism regulated by reactive oxygen species (ROS) and glutamine metabolism. Solute carrier family 1 member 5 (SLC1A5), a glutamine transporter, and c-Myc play key roles in ferroptosis, forming a "ROS/c-Myc/SLC1A5" feedback loop. The aim of this study was to investigate the regulatory role of SLC1A5 in ferroptosis. In addition, we evaluated the ferroptosis inducer Erastin as a potential therapeutic agent for EMs.
METHODS: The human endometrial stromal cells (ESCs) line hEM15A was used in this study, together with a rat model of EMs. hEM15A cells and rats were treated with Erastin, with or without SLC1A5 modulation or ROS scavenging with N-acetylcysteine (NAC). Cell viability, ROS levels, glutamine metabolism, mitochondrial function, and ferroptosis markers (glutathione peroxidase 4 (GPX4)) were subsequently analyzed by Cell Counting Kit-8 (CCK-8) assay, reverse transcription quantitative polymerase chain reaction (RT-qPCR), Western blot, and fluorescent probes. Pathological changes, lesion volumes, and pelvic adhesions in the rat EM model were assessed using hematoxylin and eosin (HE) staining, ultrasound imaging, and Haber scoring.
RESULTS: Erastin treatment of ESCs induced ferroptosis by upregulating SLC1A5 and c-Myc expression, increasing ROS levels, and altering glutamine metabolism. Overexpression of SLC1A5 enhanced sensitivity to ferroptosis, whereas SLC1A5 knockdown and NAC treatment reversed these effects. Mechanistically, c-Myc bound to the SLC1A5 promoter, forming positive feedback with ROS. In the rat model of EMs, Erastin treatment reduced ectopic lesion volume, pelvic adhesions, and inflammatory markers (TNF-α, IL-6, IL-1β). These therapeutic effects were mitigated by NAC, highlighting the importance of the ROS/c-Myc/SLC1A5 pathway.
CONCLUSIONS: This study confirmed the involvement of the ROS/c-Myc/SLC1A5 pathway in regulating EMs sensitivity to ferroptosis and demonstrated the potential of Erastin as a therapeutic agent. Targeting this pathway offers a promising approach for the treatment of EMs.

Keywords:  SLC1A5; endometriosis (EMs); ferroptosis; glutamine metabolism; reactive oxygen species (ROS)

DOI:  https://doi.org/10.31083/FBL36781
Crit Rev Oncol Hematol. 2025 Jun 03. pii: S1040-8428(25)00174-X. [Epub ahead of print] 104786

Targeting c-MYC has a Key Role in Hepatocellular Carcinoma Therapy.

Peng Dai, Liping Wang.

  Hepatocellular carcinoma (HCC) is a top cause of cancer-associated mortality worldwide, with limited effective treatment options. The oncogenic transcription factor c-MYC plays a pivotal role in HCC pathogenesis by regulating key cellular processes, including proliferation, metabolism, and apoptosis. Impaired c-MYC regulation strongly correlates with aberrant activation of multiple signaling pathways, such as PI3K/Akt/mTOR, Wnt/β-catenin, and MAPK/ERK, which collectively drive tumor progression. Furthermore, c-MYC facilitates metabolic reprogramming, enhancing glycolysis and glutamine metabolism to support rapid tumor growth. Recent advances highlight the critical interplay between c-MYC and epigenetic modulators, ubiquitination processes, and non-coding RNAs, which further sustain its oncogenic activity. Targeting c-MYC through direct inhibition, pathway-specific interventions, and combination therapies stands as a compelling option for HCC treatment. This review offers an in-depth overview of the molecular mechanisms governing c-MYC-driven hepatocarcinogenesis and explores emerging therapeutic approaches aimed at disrupting this oncogenic network. A deeper understanding of c-MYC's role in HCC will pave the way for novel treatment strategies with potential clinical applications.

Keywords:  HCC; Hepatocellular carcinoma; Liver cancer; c-MYC; drug resistance; targeted therapy; transcription factor

DOI:  https://doi.org/10.1016/j.critrevonc.2025.104786
Sci Rep. 2025 Jun 04. 15(1): 19506

2D versus 3D tumor-on-chip models to study the impact of tumor organization on metabolic patterns in vitro.

Paula Guerrero-López, Ana Martín-Pardillos, Javier Bonet-Aleta, Andrea Mosseri, Jose L Hueso, Jesus Santamaria, Jose Manuel Garcia-Aznar.

  Despite the limitations of in vitro models to investigate cancer cell metabolism, their study can provide new insights essential for understanding tumorigenesis and effectively aiding in the development of novel therapies. The innovative tumor-on-chip models offer a more physiologically relevant platform than the traditional 2D cultures. These 3D cultures incorporate cell-cell and cell-matrix interactions, as well as diffusion dynamics through both the matrix and tumor spheroid, modeling in vivo diffusion within the tumor. Therefore, this work focuses on a quantitative comparison between 2D and 3D cultures through a microfluidic chip that allows daily monitoring of cancer cell key metabolites such as glucose, glutamine and lactate, unveiling critical differences. Our analysis reveals reduced proliferation rates in 3D models, likely due to limited diffusion of nutrients and oxygen. Additionally, 3D cultures showed distinct metabolic profiles, including elevated glutamine consumption under glucose restriction and higher lactate production, indicating an enhanced Warburg effect. The microfluidic chip enabled continuous monitoring, revealing increased per-cell glucose consumption in 3D models, highlighting fewer but more metabolically active cells than in 2D cultures. These findings underscore the importance of using microfluidic-based 3D models to provide a more accurate representation of tumor metabolism and progression compared to traditional 2D cultures.

Keywords:  2D cell culture; 3D cell culture; Cancer; Glucose; Metabolism; Spheroid

DOI:  https://doi.org/10.1038/s41598-025-03504-8
Front Oncol. 2025 ;15 1564226

Metabolic reprogramming and therapeutic targeting in non-small cell lung cancer: emerging insights beyond the Warburg effect.

Hong Cai, Feng Zhang, Fang Xu, Chunhui Yang.

  Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. Recent advancements have illuminated the intricate metabolic reprogramming that underpins NSCLC progression and resistance to therapy. Beyond the classical Warburg effect, emerging evidence highlights the pivotal roles of altered lipid metabolism, amino acid utilization, and the metabolic crosstalk within the tumor microenvironment (TME). This review delves into the latest discoveries in NSCLC metabolism, emphasizing novel pathways and mechanisms that contribute to tumor growth and survival. We critically assess the interplay between cancer cell metabolism and the TME, explore the impact of metabolic heterogeneity, and discuss how metabolic adaptations confer therapeutic resistance. By integrating insights from cutting-edge technologies such as single-cell metabolomics and spatial metabolomics, we identify potential metabolic vulnerabilities in NSCLC. Finally, we propose innovative therapeutic strategies that target these metabolic dependencies, including combination approaches that enhance the efficacy of existing treatments and pave the way for personalized metabolic therapies.

Keywords:  metabolic reprogramming; metabolic vulnerabilities; non-small cell lung cancer; therapeutic targeting; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2025.1564226
bioRxiv. 2025 May 20. pii: 2025.05.15.654370. [Epub ahead of print]

Sustained Glucose Turnover Flux Distinguishes Cancer Cachexia from Nutrient Limitation.

Young-Yon Kwon, Yanshan Liang, Maria Gomez-Jenkins, Mujmmail Ahmed, Guangru Jiang, Juliya Hsiang, David Y Lewis, Tobias Janowitz, Marcus D Goncalves, Eileen White, Sheng Hui.

Cancer cachexia is an involuntary weight loss condition characterized by systemic metabolic disorder. A comprehensive flux characterization of this condition however is lacking. Here, we systematically isotope traced eight major circulating nutrients in mice bearing cachectic C26 tumors (cxC26) and food intake-matched mice bearing non-cachectic C26 tumors (ncxC26). We found no difference in whole-body lipolysis and proteolysis, ketogenesis, or fatty acid and ketone oxidation by tissues between the two groups. In contrast, compared to ncxC26 mice ad libitum, glucose turnover flux decreased in food intake-controlled ncxC26 mice but not in cxC26 mice. Similarly, sustained glucose turnover flux was observed in two autochthonous cancer cachexia models despite reduced food intake. We identified glutamine and alanine as responsible for sustained glucose production and tissues with altered use of glucose and lactate in cxC26 mice. We provide a comprehensive view of metabolic alterations in cancer cachexia revealing those distinct from decreased nutrient intake.
Highlights: Quantitative fluxomics of cancer cachexia under matched food intake and body weightIntact lipolysis, proteolysis, ketogenesis, and lipid oxidation in cachectic miceSustained glucose consumption in cachectic mice despite reduced food intakeIncreased glucose production from glutamine and alanine in cachectic mice.

DOI: https://doi.org/10.1101/2025.05.15.654370
Cell Signal. 2025 May 29. pii: S0898-6568(25)00318-3. [Epub ahead of print]134 111903

Cancer stem cells amino acid metabolism: Roles, mechanisms, and intervention strategies.

Yi Gong, Xirui Wang, Wenlong Chen, Hsiang-I Tsai, Yanfang Liu.

  Cancer stem cells (CSCs) are recognized as key drivers of tumor recurrence and therapy resistance due to their capacity for self-renewal and differentiation. Amino acid metabolic reprogramming, a hallmark of cancer, underpins CSC biology. Methionine, tryptophan, and glutamine support CSC survival and the maintenance of stemness, while proline plays a role in CSC differentiation and susceptibility to cell death. Consequently, the impact of amino acid metabolism on CSCs is multifaceted and complex. This review first outlines the intrinsic amino acid metabolic features of CSCs. It then provides a comprehensive analysis of the distinct roles of various amino acids in regulating CSC biology. Additionally, strategies targeting amino acid metabolism to eliminate CSCs in clinical therapies are discussed, offering new perspectives for the development of innovative tumor-targeting approaches.

Keywords:  Amino acid metabolism; Cancer stem cells; Therapeutic resistance; Tumor heterogeneity

DOI:  https://doi.org/10.1016/j.cellsig.2025.111903
Discov Oncol. 2025 Jun 05. 16(1): 1009

Glutamate promotes triple-negative breast cancer development through IRE1α/XBP1-mediated macrophage polarization: mechanism insights and therapy.

Hao Wang, Jifeng Sun, Zhansheng Jiang, Zhongsheng Tong, Chen Wang.

   BACKGROUND: Triple-negative breast cancer (TNBC) is a highly aggressive malignancy associated with early recurrence, metastatic propensity, and poor clinical outcomes, yet its underlying molecular mechanisms remain incompletely elucidated. This study aims to investigate the role of glutamate in promoting macrophage polarization and TNBC progression via the IRE1α/XBP-1 signaling pathway.
METHODS: The growth and pathological changes of tumor and the protein expression levels of p-PERK, ATF6, IRE1α, XBP-1, G-CSF, GM-CSF, arginase-1, CD206, iNOS and TNF-α in tumor cells were observed in vivo experiments. The expression levels of IL-6, G-CSF and GM-CSF in MCF-7 cells and MDA-MB-231 cells as well as cell proliferation, migration, invasion and cell viability were observed in vitro experiments.
RESULTS: In the vivo experiments, compared with common breast cancer tumors and TNBC tumors without overexpressing glutaminase 1 (GLS1), the tumor volume of TNBC with overexpressing GLS1 increased significantly, and the tissue necrosis increased (p < 0.05). After GLS1 overexpression, the levels of P-PERK, ATF6, IRE1α, XBP-1, G-CSF, GM-CSF, arginase-1 and CD206 in TNBC tumors significantly increased, while the levels of iNOS and TNF-α significantly decreased (p < 0.05). In the vitro experiments, compared to MCF-7 cells and MDA-MB-231 cells without the XBP-1 inhibitor toyocamycin, the levels of IL-6, G-CSF, GM-CSF, cell proliferation, migration, invasion ability, and cell viability in MDA-MB-231 cells supplemented with the XBP-1 inhibitor toyocamycin were significantly reduced (p < 0.05).
CONCLUSIONS: Glutamate can promote macrophage polarization and the development of TNBC by upregulating IRE1α/XBP-1. Targeted inhibition of glutamate metabolism or IRE1α/XBP-1 pathway can effectively block the proliferation of TNBC tumor cells, providing a basis for the study of targeted drugs to treat TNBC.

Keywords:  IRE1α; Macrophage; Triple-negative breast cancer; XBP-1

DOI:  https://doi.org/10.1007/s12672-025-02790-y
Neuron. 2025 Jun 04. pii: S0896-6273(25)00314-9. [Epub ahead of print]113(11): 1651-1652

Combining old with new: A novel approach to studying human brain metabolism.

Tyler Blazey, Manu S Goyal.

In this issue of Neuron, Wang et al. provide a detailed assessment of the metabolites and lipids utilized by the whole human brain. They report that the brain consumes glucose, lactate, glutamate, and triglycerides while producing glutamine, pyruvate, and free fatty acids.

DOI: https://doi.org/10.1016/j.neuron.2025.04.031
Front Immunol. 2025 ;16 1575829

Single-cell and bulk transcriptome analyses reveal elevated amino acid metabolism promoting tumor-directed immune evasion in colorectal cancer.

Tianyue Sun, Yan Chen, Ying-Xuan Chen.

   Introduction: Colorectal cancer (CRC), the third most common cancer worldwide, often shows limited responsiveness to immunotherapy due to its predominantly immune-excluded phenotype. Despite increasing insights into the complex tumor microenvironment (TME), the metabolic heterogeneity of CRC cells and their interactions with tumor-infiltrating immune cells remain poorly understood.
Methods: We analyzed 46,374 epithelial cells from 17 CRC patients treated with PD-1 blockade to develop an amino acid (AA) metabolism score using the AUCell algorithm. This score was applied to a separate single-cell RNA sequencing (scRNA-seq) dataset from 23 CRC patients to investigate cell-cell interactions and functions of tumor-infiltrating immune cells, revealing distinct immune TME landscapes shaped by tumor metabolism. An in vitro co-culture assay of CRC cells and CD8+ T cells was performed to validate the findings. Additionally, LASSO and Cox regression analyses were conducted to construct an AA metabolism-related risk score for predicting prognosis and drug sensitivity across multiple bulk transcriptome cohorts.
Results: This study identified a link between elevated amino acid metabolism in CRC epithelial cells and resistance to PD-1 blockade therapy. A 31-gene AA score was developed by intersecting differentially expressed genes between responders and non-responders to PD-1 blockade with amino acid metabolism-related genes from the Molecular Signature Database (MSigDB). Using this score, 23 additional CRC samples were classified into high and low AA score groups. Comparative analysis revealed that the low AA group exhibited a more robust immune response, characterized by a greater number and stronger cell-cell interactions. Tumor-infiltrating immune cells in this group demonstrated enhanced activation and anti-tumor functions. Furthermore, CD8+ T cells showed increased Granzyme B levels when co-cultured with CRC cells in which Psat1 or Shmt2 was knocked down. Finally, a machine learning-derived risk score based on six genes was established to translate single-cell findings to bulk transcriptomes. This risk score was found to correlate with immune checkpoint expression and immune cell infiltration, with potential implications for predicting prognosis and drug sensitivity.
Conclusion: Our findings highlight the role of elevated epithelial amino acid metabolism in shaping an immune-suppressive microenvironment, offering insights for patient stratification and therapeutic decision-making.

Keywords:  amino acid metabolism; colorectal cancer; immunotherapy; single cell RNA and transcriptome sequencing; tumor immune evasion; tumor metabolic reprogramming

DOI:  https://doi.org/10.3389/fimmu.2025.1575829