bims-glucam 2025-01-26 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–01–26
twenty-one papers selected by
Sreeparna Banerjee, Middle East Technical University

Targeting Glutamine Metabolic Reprogramming in Pancreatic Cancer: Current Insights and Future Directions.
SLC1A5 is a key regulator of glutamine metabolism and a prognostic marker for aggressive luminal breast cancer.
Mechanism Study of E2F8 Activation of SPC25-Mediated Glutamine Metabolism Promoting Immune Escape in Lung Adenocarcinoma.
Metabolic shifts in glioblastoma: unraveling altered pathways and exploring novel therapeutic avenues.
Wall shear stress modulates metabolic pathways in endothelial cells.
Drug Repurposing: A Conduit to Unravelling Metabolic Reprogramming for Cancer Treatment.
Fuel for thought: targeting metabolism in lung cancer.
Restriction of mitochondrial oxidation of glutamine or fatty acids enhances intracellular growth of Mycobacterium abscessus in macrophages.
KNTC1 introduces segmental heterogeneity to mitochondria.
Glutamine-glutamate centered metabolism as the potential therapeutic target against Japanese encephalitis virus-induced encephalitis.
Impaired oxidative phosphorylation drives primary tumor escape and metastasis.
Glutamine, Serine and Glycine at Increasing Concentrations Regulate Cisplatin Sensitivity in Gastric Cancer by Posttranslational Modifications of KDM4A.
Development of an attenuated glutamine synthetase (GS) selection system for the stable expression of tissue plasminogen activator in CHO-K1 cells.
Liver lipid metabolism, oxidative stress, and inflammation in glutamine-supplemented ob/ob mice.
Tracing of Amino Acids Dynamics in Cell Lines Based on 18O Stable Isotope Labeling.
Significance of birth in the maintenance of quiescent neural stem cells.
Platelet membrane biomimetic nanomedicine induces dual glutathione consumption for enhancing cancer radioimmunotherapy.
Evaluation of Anticancer Activity of Novel and Tumor-Targeted Glutamine-Conjugated Organotin(IV) Compounds in Colorectal Cancer─An In Vitro and In Vivo Study.
The roles of IDH2 and glutathione metabolism in cetuximab resistance in head and neck squamous cell carcinoma investigated by metabolomics and transcriptomics.
Metabolic interplays between the tumour and the host shape the tumour macroenvironment.
Glutamine Synthetase: Diverse Regulation and Functions of an Ancient Enzyme.

Curr Cancer Drug Targets. 2025 Jan 22.

Targeting Glutamine Metabolic Reprogramming in Pancreatic Cancer: Current Insights and Future Directions.

Yanhui Ma, Mingling Wang, Kexing Zhang, Fangbing Ren, Yuqun Wang, Wenqiang Zhang, Chengxia Kan, Fang Han, Hongxi Sun, Xiaodong Sun.

  Pancreatic Cancer (PC) is a devastating malignancy with a poor prognosis and in-creasing morbidity. Current treatment strategies have limited efficacy in improving patient survival. Metabolic reprogramming is a hallmark of cancer and plays a key role in the pro-gression and maintenance of PC. PC cells exhibit a unique glutamine metabolism that is dis-tinct from other cancer types. The non-classical pathway of glutamine metabolic reprogram-ming plays a "permissive role" in the survival and proliferation of PC cells, mainly by affect-ing the redox homeostasis of the cells. In this review, we compare and contrast the canonical and non-canonical glutamine metabolic pathways and highlight recent advances in targeting non-canonical glutamine metabolism for therapeutic intervention. This may provide novel in-sights and opportunities for exploiting glutamine metabolic reprogramming in PC treatment.

Keywords:  Pancreatic cancer; glutamine metabolism; glutamine metabolism inhibitors; metabolic reprogramming; targeted treat-ment.

DOI:  https://doi.org/10.2174/0115680096357993241206072609
Sci Rep. 2025 Jan 22. 15(1): 2805

SLC1A5 is a key regulator of glutamine metabolism and a prognostic marker for aggressive luminal breast cancer.

Lutfi H Alfarsi, Rokaya El Ansari, Busra Erkan, Ali Fakroun, Madeleine L Craze, Mohammed A Aleskandarany, Kiu Wai Cheng, Ian O Ellis, Emad A Rakha, Andrew R Green.

  Cancer cells exhibit altered metabolism, often relying on glutamine (Gln) for growth. Breast cancer (BC) is a heterogeneous disease with varying clinical outcomes. We investigated the role of the amino acid transporter SLC1A5 (ASCT2) and its association with BC subtypes and patient outcomes. In large BC cohorts, SLC1A5 mRNA (n = 9488) and SLC1A5 protein (n = 1274) levels were assessed and correlated their expression with clinicopathological features, molecular subtypes, and patient outcomes. In vitro SLC1A5 knockdown and inhibition studies in luminal BC cell lines (ZR-75-1 and HCC1500) were used to further explore the role of SLC1A5 in Gln metabolism. Statistical analysis was performed using chi-squared tests, ANOVA, Spearman's correlation, Kaplan-Meier analysis, and Cox regression. SLC1A5 mRNA and SLC1A5 protein expression were strongly correlated in luminal B, HER2 + and triple-negative BC (TNBC). Both high SLC1A5 mRNA and SLC1A5 protein expression were associated with larger tumour size, higher grade, and positive axillary lymph node metastases (P < 0.01). Importantly, high SLC1A5 expression correlated with poor BC-specific survival specifically in the highly proliferative luminal subtype (P < 0.001). Furthermore, SLC1A5 knockdown by siRNA or GPNA inhibition significantly reduced cell proliferation and glutamine uptake in ZR-75-1 cells. Our findings suggest SLC1A5 plays a key role in the aggressive luminal BC subtype and represents a potential therapeutic target. Further research is needed to explore SLC1A5 function in luminal BC and its association with Gln metabolism pathways.

Keywords:  Breast cancer; Prognosis; SLC1A5; Tumour marker

DOI:  https://doi.org/10.1038/s41598-025-87292-1
Immunology. 2025 Jan 19.

Mechanism Study of E2F8 Activation of SPC25-Mediated Glutamine Metabolism Promoting Immune Escape in Lung Adenocarcinoma.

Machang Luo, Lingyan Xie, Baoyan Lin, Xia Su, Rongzhang Liang, Zhiyi Ma, Youtang Li.

  Tumour cell immune infiltration is linked to spindle pole component 25 (SPC25). The purpose of this work was to examine the function and molecular mechanism of SPC25 in immune escape in lung adenocarcinoma (LUAD). SPC25 expression in LUAD was examined using The Cancer Genome Atlas (TCGA) database, and RT-qPCR was used to confirm the results. The study involved the use of CD8+ T lymphocytes for immunoinfiltration analysis of SPC25, Gene Set Enrichment Analysis (GSEA) analysis of signalling pathways enriched by SPC25, identification of putative regulatory molecules of SPC25, and confirmation through the use of dual-luciferase and ChIP tests. To evaluate LUAD cell capacity for immune escape, a co-culture technique was employed. Measurements of glutamine uptake, glutamate and α-ketoglutarate levels, NADPH/NADP and GSH/GSSG ratios, and SLC1A5 expression were used to assess the levels of glutamine metabolism. LUAD had increased SPC25 expression. In LUAD cells, immune escape was facilitated by SPC25 knockdown, whereas overexpression had the reverse effect. SPC25 enrichment in the glutamine metabolism pathway was shown by GSEA analysis. Through increased glutamine metabolism brought on by SPC25 overexpression, immune escape was improved in LUAD and could be mitigated by GPNA therapy. E2F8 was also shown to be the transcription factor associated with SPC25, and they showed a binding interaction. By inhibiting glutamine metabolism through SPC25, knocking down E2F8 prevented immune escape in LUAD cells. On the other hand, the suppression of immune escape in LUAD cells caused by E2F8 knockdown was overcome by overexpression of SPC25. In LUAD, E2F8 stimulates SPC25 expression to facilitate glutamine metabolism and encourage immune escape. Our research validates a novel immune escape pathway driven by SPC25 in LUAD cells, providing LUAD patients with potentially effective immunotherapeutic approaches.

Keywords:  E2F8; SPC25; glutamine metabolism; immune escape; lung adenocarcinoma

DOI:  https://doi.org/10.1111/imm.13894
Mol Biol Rep. 2025 Jan 22. 52(1): 146

Metabolic shifts in glioblastoma: unraveling altered pathways and exploring novel therapeutic avenues.

Dinky Malhotra, Reema Gabrani.

  Metabolic reprogramming stands out as a defining characteristic of cancer, including glioblastoma (GB), enabling tumor cells to overcome growth and survival challenges in adverse conditions. The dysregulation of metabolic processes in GB is crucial to its pathogenesis, influencing both tumorigenesis and the disease's invasive tendencies. This altered metabolism supplies essential energy substrates for uncontrolled cell proliferation and also creates an immunosuppressive microenvironment, complicating conventional therapies. A comprehensive understanding of the complexities of metabolic dysregulation in carbohydrate, amino acid, lipid and nucleotide pathways in GB holds promise for effective therapeutic interventions. Key metabolic enzymes, transporters, and signaling pathways and mitochondrial metabolism have been examined for their roles in GB pathology and their possible therapeutic potential. Addressing these metabolic targets has shown efficacy in preclinical models and is currently being evaluated in clinical trials. Combination therapies that exploit metabolic vulnerabilities alongside conventional treatments hold the promise of improving patient outcomes. This review explores the dynamic interplay between glioblastoma's aggressiveness and altered metabolism, offering insights into potential therapeutic strategies. Moreover, this review discusses the recent advancements in drug development aimed at targeting these dysregulated metabolic pathways.

Keywords:  Altered metabolism; Carbohydrate metabolism; Combination therapies; Glutamine; Lipid metabolism; Metabolic reprogramming

DOI:  https://doi.org/10.1007/s11033-025-10242-7
Metabolomics. 2025 Jan 20. 21(1): 16

Wall shear stress modulates metabolic pathways in endothelial cells.

Rita Simões-Faria, Margo Daems, Hanna M Peacock, Mathias Declercq, Anton Willems, Elizabeth A V Jones, Bart Ghesquière.

   INTRODUCTION: Hemodynamic forces play a crucial role in modulating endothelial cell (EC) behavior, significantly influencing blood vessel responses. While traditional in vitro studies often explore ECs under static conditions, ECs are exposed to various hemodynamic forces in vivo. This study investigates how wall shear stress (WSS) influences EC metabolism, focusing on the interplay between WSS and key metabolic pathways.
OBJECTIVES: The aim of this study is to examine the effects of WSS on EC metabolism, specifically evaluating its impact on central carbon metabolism and glycolysis using transcriptomics and tracer metabolomics approaches.
METHODS: ECs were exposed to WSS, and transcriptomic analysis was performed to assess gene expression changes related to metabolic pathways. Tracer metabolomics was used to track metabolic fluxes, focusing on glutamine and glycolytic metabolism. Additionally, chemical inhibition of glutamate dehydrogenase was conducted to evaluate its role in EC fitness under WSS.
RESULTS: Transcriptomic data revealed upregulation of glutamine and glutamate pathways, alongside downregulation of glycolytic activity in ECs exposed to WSS. Tracer metabolomics confirmed that WSS promotes glutamine anaplerosis into the Krebs cycle, while decreasing glycolytic metabolism. Suppression of glutamate dehydrogenase impaired EC fitness under WSS conditions.
CONCLUSION: Our findings illuminate that ECs subjected to WSS exhibit a preference for glutamine as a key nutrient source for central carbon metabolism pathways, indicating diminished reliance on glycolysis. This study elucidates the nutritional predilections and regulatory mechanisms governing EC metabolism under WSS in vitro, underscoring the pivotal role of physical stimuli in shaping EC metabolic responses.

Keywords:  Endothelial cells; Glutamate dehydrogenase; Glutamine; Shear stress; Tracer metabolomics

DOI:  https://doi.org/10.1007/s11306-024-02214-y
Mini Rev Med Chem. 2025 Jan 17.

Drug Repurposing: A Conduit to Unravelling Metabolic Reprogramming for Cancer Treatment.

Shristy Chaudhary, Abhilash Rana, Seema Bhatnagar.

  Metabolic reprogramming is a hallmark of cancer. Distinct and unusual metabolic aberrations occur during tumor development that lead to the growth and development of tumors. Oncogenic signaling pathways eventually converge to regulate three major metabolic pathways in tumor cells i.e., glucose, lipid, and amino acid metabolism. Therefore, identifying and targeting the metabolic nodes of cancer cells can be a promising intervention and therapeutic strategy for patients with malignancies. The long road of new drug discovery for cancer therapy has necessitated relooking alternative strategies such as drug repurposing. Advanced genomic and proteomic technologies for the assessment of cancer-specific biological pathways have led to the discovery of new drug targets, which provide excellent opportunities for drug repurposing. The development of effective, safe, cheaper, and readily available anticancer agents is the need of the hour, and drug repurposing has the potential to break the current drug shortage bottleneck. This review will accordingly cover various metabolic pathways that are aberrant in cancer, and strategies for targeting metabolic reprogramming by using repurposed drugs.

Keywords:  Drug repurposing; cancer; cancer metabolism; cancer treatment; cell deathh; metabolic reprogramming

DOI:  https://doi.org/10.2174/0113895575339660250106093738
Transl Lung Cancer Res. 2024 Dec 31. 13(12): 3692-3717

Fuel for thought: targeting metabolism in lung cancer.

Jaime L Schneider, SeongJun Han, Christopher S Nabel.

  For over a century, we have appreciated that the biochemical processes through which micro- and macronutrients are anabolized and catabolized-collectively referred to as "cellular metabolism"-are reprogrammed in malignancies. Cancer cells in lung tumors rewire pathways of nutrient acquisition and metabolism to meet the bioenergetic demands for unchecked proliferation. Advances in precision medicine have ushered in routine genotyping of patient lung tumors, enabling a deeper understanding of the contribution of altered metabolism to tumor biology and patient outcomes. This paradigm shift in thoracic oncology has spawned a new enthusiasm for dissecting oncogenotype-specific metabolic phenotypes and creates opportunity for selective targeting of essential tumor metabolic pathways. In this review, we discuss metabolic states across histologic and molecular subtypes of lung cancers and the additional changes in tumor metabolic pathways that occur during acquired therapeutic resistance. We summarize the clinical investigation of metabolism-specific therapies, addressing successes and limitations to guide the evaluation of these novel strategies in the clinic. Beyond changes in tumor metabolism, we also highlight how non-cellular autonomous processes merit particular consideration when manipulating metabolic processes systemically, such as efforts to disentangle how lung tumor cells influence immunometabolism. As the future of metabolic therapeutics hinges on use of models that faithfully recapitulate metabolic rewiring in lung cancer, we also discuss best practices for harmonizing workflows to capture patient specimens for translational metabolic analyses.

Keywords:  Lung cancer; immunometabolism; metabolism; resistance

DOI:  https://doi.org/10.21037/tlcr-24-662
Virulence. 2025 Dec;16(1): 2454323

Restriction of mitochondrial oxidation of glutamine or fatty acids enhances intracellular growth of Mycobacterium abscessus in macrophages.

Ho Won Kim, Ji Won Lee, Hoe Sun Yoon, Hwan-Woo Park, Young Ik Lee, Sung Ki Lee, Jake Whang, Jong-Seok Kim.

  Mycobacterium abscessus (Mab), a nontuberculous mycobacterium, is increasing in prevalence worldwide and causes treatment-refractory pulmonary diseases. However, how Mab rewires macrophage energy metabolism to facilitate its survival is poorly understood. We compared the metabolic profiles of murine bone marrow-derived macrophages (BMDMs) infected with smooth (S)- and rough (R)-type Mab using extracellular flux technology. Mab infection shifted BMDMs towards a more energetic phenotype, marked by increased oxidative phosphorylation (OXPHOS) and glycolysis, with a significantly greater enhancement in OXPHOS. This metabolic adaptation was characterized by enhanced ATP production rates, particularly in cells infected with S-type Mab, highlighting OXPHOS as a key energy source. Notably, Mab infection also modulated mitochondrial substrate preferences, increasing fatty acid oxidation capabilities while revealing significant changes in glutamine dependency and flexibility. R-type Mab infections exhibited a marked decrease in glutamine reliance but enhanced metabolic flexibility and capacity. Furthermore, targeting metabolic pathways related to glutamine and fatty acid oxidation exacerbated Mab growth within macrophages, suggesting these pathways play a protective role against infection. These insights advance our understanding of Mab's impact on host cell metabolism and propose a novel avenue for therapeutic intervention. By manipulating host mitochondrial metabolism, we identify a potential host-directed therapeutic strategy against Mab, offering a promising alternative to conventional treatments beleaguered by drug resistance. This study underscores the importance of exploring metabolic interventions to combat Mab infection, paving the way for innovative approaches in the fight against this formidable pathogen.

Keywords:  Mycobacterium abscessus; OXPHOS; glycolysis; metabolism

DOI:  https://doi.org/10.1080/21505594.2025.2454323
Dis Model Mech. 2025 Jan 20. pii: dmm.052063. [Epub ahead of print]

KNTC1 introduces segmental heterogeneity to mitochondria.

Atsushi Tsukamura, Hirotaka Ariyama, Natsuki Hayashi, Satoko Miyatake, Satoko Okado, Sara Sultana, Ichiro Terakado, Takefumi Yamamoto, Shoji Yamanaka, Satoshi Fujii, Haruka Hamanoue, Ryoko Asano, Taichi Mizushima, Naomichi Matsumoto, Yoshihiro Maruo, Masaki Mori.

  Mitochondria contribute to cellular metabolism by providing a specialised milieu for energising cells by incorporating and processing the metabolites. However, heterogeneity in the mitochondria within is only partially elucidated. Mitochondria dynamically alter their morphology and functions during the life of animals, in which cells proliferate and grow. We here show that Kntc1, a highly evolutionarily conserved protein, translocates from the Golgi apparatus to linear mitochondrial segments (LMS) upon glutamine deprivation and plays an essential role in maintaining LMS. The LMS with Kntc1 localisation exhibits an increase in the membrane potential, suggesting the role of Kntc1 in functioning as a reservoir for the energy-generating potential. Suppression of Kntc1 leads to glutamine consumption and lactate production, thus impacting cellular metabolism, eventually leading to anchorage-independent growth of cells. Indeed, the KNTC1 variant was identified in a patient with ovarian cancer, suggesting that segmental regulation of the mitochondrial function is essential for maintaining tissue integrity.

Keywords:  Bent mitochondrial segment (BMS); Glutamine metabolism; KNTC1; Linear mitochondrial segment (LMS); Mitochondrial structural heterogeneity

DOI:  https://doi.org/10.1242/dmm.052063
Cell Biosci. 2025 Jan 22. 15(1): 6

Glutamine-glutamate centered metabolism as the potential therapeutic target against Japanese encephalitis virus-induced encephalitis.

Mengyuan Li, Hang Yuan, Xiaofei Yang, Yingfeng Lei, Jianqi Lian.

   BACKGROUND: Japanese encephalitis (JE) induced by Japanese encephalitis virus (JEV) infection is the most prevalent diagnosed epidemic viral encephalitis globally. The underlying pathological mechanisms remain largely unknown. Given that viruses are obligate intracellular parasites, cellular metabolic reprogramming triggered by viral infection is intricately related to the establishment of infection and progression of disease. Therefore, uncovering and manipulating the metabolic reprogramming that underlies viral infection will help elucidate the pathogenic mechanisms and develop novel therapeutic strategies.
METHODS: Metabolomics analysis was performed to comprehensively delineate the metabolic profiles in JEV-infected mice brains and neurons. Metabolic flux analysis, quantitative real-time PCR, western blotting and fluorescence immunohistochemistry were utilized to describe detailed glutamine-glutamate metabolic profiles during JEV infection. Exogenous addition of metabolites and associated compounds and RNA interference were employed to manipulate glutamine-glutamate metabolism to clarify its effects on viral replication. The survival rate, severity of neuroinflammation, and levels of viral replication were assessed to determine the efficacy of glutamine supplementation in JEV-challenged mice.
RESULTS: Here, we have delineated a novel perspective on the pathogenesis of JE by identifying an aberrant low flux in glutamine-glutamate metabolism both in vivo and in vitro, which was critical in the establishment of JEV infection and progression of JE. The perturbed glutamine-glutamate metabolism induced neurotransmitter imbalance and created an immune-inhibitory state with increased gamma-aminobutyric acid/glutamate ratio, thus facilitating efficient viral replication both in JEV-infected neurons and the brain of JEV-infected mice. In addition, viral infection restrained the utilization of glutamine via the glutamate-α-ketoglutaric acid axis in neurons, thus avoiding the adverse effects of glutamine oxidation on viral propagation. As the conversion of glutamine to glutamate was inhibited after JEV infection, the metabolism of glutathione (GSH) was simultaneously impaired, exacerbating oxidative stress in JEV-infected neurons and mice brains and promoting the progression of JE. Importantly, the supplementation of glutamine in vivo alleviated the intracranial inflammation and enhanced the survival of JEV-challenged mice.
CONCLUSION: Altogether, our study highlights an aberrant glutamine-glutamate metabolism during JEV infection and unveils how this facilitates viral replication and promotes JE progression. Manipulation of these metabolic alterations may potentially be exploited to develop therapeutic approaches for JEV infection.

Keywords:  Japanese encephalitis virus; Metabolism; Viral encephalitis

DOI:  https://doi.org/10.1186/s13578-024-01340-3
bioRxiv. 2025 Jan 09. pii: 2025.01.08.631936. [Epub ahead of print]

Impaired oxidative phosphorylation drives primary tumor escape and metastasis.

Emily N Arner, Erin Q Jennings, Daniel R Crooks, Christopher J Ricketts, Melissa M Wolf, Matthew A Cottam, Emilie L Fisher-Gupta, Martin Lang, Nunziata Maio, Yuki Shibata, Evan S Krystofiak, Logan M Vlach, Zaid Hatem, Alexander M Blatt, Darren R Heintzman, Allison E Sewell, Emma S Hathaway, KayLee K Steiner, Xiang Ye, Samuel Schaefer, Zachary A Bacigalupa, W Marston Linehan, Kathryn E Beckermann, Frank M Mason, Kamran Idrees, W Kimryn Rathmell, Jeffrey C Rathmell.

Metastasis causes most cancer deaths and reflects transitions from primary tumor escape to seeding and growth at metastatic sites. Epithelial-to-mesenchymal transition (EMT) is important early in metastasis to enable cancer cells to detach from neighboring cells, become migratory, and escape the primary tumor. While different phases of metastasis expose cells to variable nutrient environments and demands, the metabolic requirements and plasticity of each step are uncertain. Here we show that EMT and primary tumor escape are stimulated by disrupted oxidative metabolism. Using Renal Cell Carcinoma (RCC) patient samples, we identified the mitochondrial electron transport inhibitor NDUFA4L2 as upregulated in cells undergoing EMT. Deletion of NDUFA4L2 enhanced oxidative metabolism and prevented EMT and metastasis while NDUFA4L2 overexpression enhanced these processes. Mechanistically, NDUFA4L2 suppressed oxidative phosphorylation and caused citric acid cycle intermediates to accumulate, which modified chromatin accessibility of EMT-related loci to drive primary tumor escape. The effect of impaired mitochondrial metabolism to drive EMT appeared general, as renal cell carcinoma patient tumors driven by fumarate hydratase mutations with disrupted oxidative phosphorylation were highly metastatic and also had robust EMT. These findings highlight the importance of dynamic shifts in metabolism for cell migration and metastasis, with mitochondrial impairment driving early phases of this process. Understanding mitochondrial dynamics may have important implications in both basic and translational efforts to prevent cancer deaths.

DOI: https://doi.org/10.1101/2025.01.08.631936
Mol Carcinog. 2025 Jan 21.

Glutamine, Serine and Glycine at Increasing Concentrations Regulate Cisplatin Sensitivity in Gastric Cancer by Posttranslational Modifications of KDM4A.

Junhao Fu, Yuqi Ni, Yuqing Hu, Wanfen Tang, Jianfei Fu, Yue Wang, Shian Yu, Wenxia Xu.

  Gastric cancer is a common digestive system tumor with a high resistance rate that reduces the sensitivity to chemotherapy. Nutrition therapy is an important adjuvant approach to favor the prognosis of gastric cancer. Dietary amino acids contribute greatly to gastric cancer progression by mediating tumor gene expressions, epigenetics, signal transduction, and metabolic remodeling. In the present study, 20 types of amino acids were screened and glutamine, glycine and serine were identified as the critical regulators of cisplatin (DDP) sensitivity in gastric cancer cells. Moreover, KDM4A acetylation drove the reduced chemotherapy sensitivity in gastric cancer cells by maintaining protein stability and activating DNA repair ability when the concentrations of glutamine (Gln), serine (Ser), and glycine (Gly) decreased. Conversely, Gln/Ser/Gly at increasing concentrations stimulated ubiquitination degradation of KDM4A, which in turn elevated the sensitivity of gastric cancer cells to chemotherapy. Our findings unveiled the role of amino acid nutrition in regulating chemotherapy sensitivity of gastric cancer and the underlying mechanism, thus providing a scientific basis for expanding the clinical significance of nutrition therapy for gastric cancer patients.

Keywords:  KDM4A; gastric cancer; glutamine; glycine; serine

DOI:  https://doi.org/10.1002/mc.23881
Prep Biochem Biotechnol. 2025 Jan 21. 1-7

Development of an attenuated glutamine synthetase (GS) selection system for the stable expression of tissue plasminogen activator in CHO-K1 cells.

Mozhgan Raigani, Pegah Namdar, Farzaneh Barkhordari, Sima Sadat Seyedjavadi, Azam Rahimpour, Ahmad Adeli.

  Chinese hamster ovary (CHO) cells represent the most common host system for the expression of high-quality recombinant proteins. The development of stable CHO cell lines used in industrial recombinant protein production often relies on dihydrofolate reductase (DHFR) and glutamine synthetase (GS) amplification systems. Conventional approaches to develop stable cell lines lead to heterogeneous cell populations. Consequently, it is desirable to adopt innovative strategies to increase the efficiency of clone selection to reduce the time and effort invested in the cell line development process. Attenuating the selection marker gene is an effective strategy for isolating high-producing cells. In this study, we evaluated the efficiency of an attenuated glutamine synthetase selection system for the expression of human tissue plasminogen activator (t-PA) in CHO cells. We introduced an AU-rich element (ARE) at the 3'UTR of the glutamine synthetase coding sequence and employed a weak promoter (mSV40) for the expression of this gene. Subsequently, we analyzed the effect of ARE on the GS RNA levels, and recombinant t-PA expression. Our results demonstrate that the use of ARE significantly enhances the detection of high expressing cells compared to the control. Additionally, the t-PA expression level in GS-ARE clones was approximately 900-fold greater than those without the ARE.

Keywords:  AU-rich element; Cell line development; Chinese hamster ovary (CHO); glutamine synthetase (GS); mSV40

DOI:  https://doi.org/10.1080/10826068.2025.2454335
J Nutr Biochem. 2025 Jan 15. pii: S0955-2863(25)00005-1. [Epub ahead of print] 109842

Liver lipid metabolism, oxidative stress, and inflammation in glutamine-supplemented ob/ob mice.

Jaqueline Santos Moreira Leite, Eloisa Aparecida Vilas-Boas, Hilton K Takahashi, Ana Cláudia Munhoz, Layanne C C Araújo, Carla Roberta Carvalho, Jose Donato Jr, Rui Curi, Angelo Rafael Carpinelli, Vinicius Cruzat.

  Glutamine availability may be reduced in chronic diseases, such as type 2 diabetes mellitus (T2DM)-induced by obesity. Herein, the antioxidant, anti-inflammatory and lipid metabolism effects of chronic oral glutamine supplementation in its free and dipeptide form were assessed in ob/ob mice. Adult male C57BL/6J ob/ob mice were supplemented with L-alanyl-L-glutamine (DIP) or free L-glutamine (GLN) in the drinking water for 40 days, whilst C57BL/6J Wild-type lean (WT) and control ob/ob mice (CTRL) received fresh water only. Plasma and tissue (skeletal muscle and liver) glutamine levels, and insulin resistance parameters (e.g., GTT, ITT, insulin) were determined. Oxidative stress (e.g., GSH system, Nrf2 translocation), inflammatory (e.g., NFkB translocation, TNF-α gene expression) and lipid metabolism parameters (e.g., plasma and liver triglyceride levels, SRBP-1, FAS, ACC, and ChRBP gene expression) were also analyzed. CTRL ob/ob mice showed lower glutamine levels in plasma and tissue, as well as increased insulin resistance and fat in the liver. Conversely, chronic DIP supplementation restored glutamine levels in plasma and tissues, improved glucose homeostasis and reduced plasma and liver lipid levels. Also, Nrf2 restoration, reduced NFkB translocation, and lower TNF-α gene expression was observed in the DIP group. Interestingly, chronic free GLN only increased muscle glutamine stores but reduced overall insulin resistance, and attenuated plasma and liver lipid metabolic biomarkers. The results presented herein indicate that restoration of body glutamine levels reduces oxidative stress and inflammation in obese and T2DM ob/ob mice. This effect attenuated hepatic lipid metabolic changes observed in obesity.

Keywords:  Diabetes; Obesity; amino acids; anti-inflammatory; antioxidant; non-alcoholic fatty liver disease

DOI:  https://doi.org/10.1016/j.jnutbio.2025.109842
Anal Chem. 2025 Jan 23.

Tracing of Amino Acids Dynamics in Cell Lines Based on 18O Stable Isotope Labeling.

Cemil Can Eylem, İpek Baysal, Samiye Yabanoğlu Çiftçi, Emirhan Nemutlu.

Metabolite levels and turnover rates are necessary to understand metabolomic dynamics in a living organism fully. Amino acids can play distinct roles in various cellular processes, and their abnormal levels are associated with pathological conditions, including cancer. Therefore, their levels, especially turnover rates, may provide enormous information about a phenotype. 13C- or 13C,15N-labeled amino acids have also been commonly used to trace amino acid metabolism. This study presented a new methodology based on 18O labeling for amino acids that relied on monitoring mass isotopologues to calculate the turnover rates of amino acids. The method optimization studies were carried over for selective amino acid monitoring. This methodology provides a rapid, robust, and simple GC-MS method for analyzing the fluxes of amino acid metabolism. The developed method was applied to fetal human colon (FHC) and human colon carcinoma (Caco-2) cell lines to determine cancer-induced shifts in the turnover rates of amino acids. These results defined metabolic reprogramming in Caco-2 cells through increased glutamate and serine turnovers and sharply decreased turnovers of aspartate, threonine, and methionine, therefore pointing to some metabolic vulnerabilities in the metabolism of cancerous cells. The simple mechanism of the developed methodology, the availability of affordable 18O-enriched water, and the ease of application can open a new arena in fluxomics analysis.

DOI: https://doi.org/10.1021/acs.analchem.4c05015
Sci Adv. 2025 Jan 24. 11(4): eadn6377

Significance of birth in the maintenance of quiescent neural stem cells.

Koya Kawase, Yasuhisa Nakamura, Laura Wolbeck, Shoko Takemura, Kei Zaitsu, Takehiro Ando, Hideo Jinnou, Masato Sawada, Chikako Nakajima, Rasmus Rydbirk, Sakura Gokenya, Akira Ito, Hitomi Fujiyama, Akari Saito, Akira Iguchi, Panagiotis Kratimenos, Nobuyuki Ishibashi, Vittorio Gallo, Osuke Iwata, Shinji Saitoh, Konstantin Khodosevich, Kazunobu Sawamoto.

Birth is one of the most important life events for animals. However, its significance in the developmental process is not fully understood. Here, we found that birth-induced alteration of glutamine metabolism in radial glia (RG), the embryonic neural stem cells (NSCs), is required for the acquisition of quiescence and long-term maintenance of postnatal NSCs. Preterm birth impairs this cellular process, leading to transient hyperactivation of RG. Consequently, in the postnatal brain, the NSC pool is depleted and neurogenesis is decreased. We also found that the maintenance of quiescent RG after preterm birth improves postnatal neurogenesis. This study demonstrates the significance of birth in the maintenance of quiescent NSCs.

DOI: https://doi.org/10.1126/sciadv.adn6377
J Pharm Anal. 2024 Dec;14(12): 100935

Platelet membrane biomimetic nanomedicine induces dual glutathione consumption for enhancing cancer radioimmunotherapy.

Xiaopeng Li, Yang Zhong, Pengyuan Qi, Daoming Zhu, Chenglong Sun, Nan Wei, Yang Zhang, Zhanggui Wang.

  Radiotherapy (RT) is one of the most common treatments for cancer. However, intracellular glutathione (GSH) plays a key role in protecting cancer from radiation damage. Herein, we have developed a platelet membrane biomimetic nanomedicine (PMD) that induces double GSH consumption to enhance tumor radioimmunotherapy. This biomimetic nanomedicine consists of an external platelet membrane and internal organic mesoporous silica nanoparticles (MON) loaded with 2-deoxy-D-glucose (2-DG). Thanks to the tumor-targeting ability of the platelet membranes, PMD can target and aggregate to the tumor site, which is internalized by tumor cells. Within tumor cells overexpressing GSH, MON reacts with GSH to degrade and release 2-DG. This step initially depletes the intracellular GSH content. The subsequent release of 2-DG inhibits glycolysis and adenosine triphosphate (ATP) production, ultimately leading to secondary GSH consumption. This nanodrug combines dual GSH depletion, starvation therapy, and RT to promote immunogenic cell death and stimulate the systemic immune response. In the bilateral tumor model in vivo, distal tumor growth was also well suppressed. The proportion of mature dendritic cells (DC) and CD8+ T cells in the mice was increased. This indicates that PMD can promote anti-tumor radioimmunotherapy and has good prospects for clinical application.

Keywords:  Cancer radioimmunotherapy; Dual GSH consumption; Organic mesoporous silica nanoparticles; Platelet membrane biomimetic nanomedicine; Starvation therapy

DOI:  https://doi.org/10.1016/j.jpha.2024.01.003
J Med Chem. 2025 Jan 21.

Evaluation of Anticancer Activity of Novel and Tumor-Targeted Glutamine-Conjugated Organotin(IV) Compounds in Colorectal Cancer─An In Vitro and In Vivo Study.

Shagun Sharma, Varinder Kaur, Pratibha Duhan, Raghubir Singh, Navneet Agnihotri.

Over the years, numerous ligand-based organotin(IV) Schiff base compounds have shown remarkable cytotoxicity and anticancer activities, but their clinical use is restricted by systemic toxicity, prompting the search for targeted therapies. Targeted delivery can be enhanced by exploiting the inherent characteristics of cancer cells such as glutamine addiction, which is essential to support cellular biosynthesis and cell growth to sustain aberrant proliferation. Our previous study revealed glutamine-conjugated organotin(IV) compounds have strong DNA/protein affinities, favorable in silico ADME profiles, and significant antiproliferative activity. In this study, these compounds demonstrated significant cytotoxicity against human colon carcinoma and adenocarcinoma cell lines via the induction of cell cycle arrest and apoptosis. In DMH/DSS-induced experimental colon carcinogenesis, these compounds reduced tumor burden and volume and inhibited cell proliferation and induced apoptosis, with minimal toxicity. Tissue distribution studies revealed selective accumulation in the colon. These findings support their potential as chemotherapeutic candidates for colon cancer.

DOI: https://doi.org/10.1021/acs.jmedchem.4c01728
Cell Signal. 2025 Jan 20. pii: S0898-6568(25)00033-6. [Epub ahead of print]127 111620

The roles of IDH2 and glutathione metabolism in cetuximab resistance in head and neck squamous cell carcinoma investigated by metabolomics and transcriptomics.

Shousen Hu, Zian Wang, Xu Ding, Daoke Yao, Yue Du, Xiangzhen Kong.

  Cetuximab resistance is a significant challenge in the treatment of head and neck squamous cell carcinoma (HNSCC). In this study, cetuximab-resistant HNSCC cell lines were established, and untargeted metabolomics was used to detect differences in metabolite profiles between sensitive and resistant cell lines. It was found that glutathione metabolism significantly differed between the sensitive and resistant lines. Combining these findings with transcriptome data, correlation analysis of metabolites revealed that IDH2 regulated glutathione metabolism and contributed to cetuximab resistance in FaDu cells. In vitro experiments showed that IDH2 was highly expressed in FaDu-CR cells, and IDH2 knockdown significantly enhanced the sensitivity of FaDu and FaDu-CR cells to cetuximab. IDH2 knockdown reduced GSH levels and GPX4 expression in FaDu and FaDu-CR cells under cetuximab treatment, while increasing lipid ROS levels. In vivo experiments demonstrated that IDH2 knockdown decreased the tumorigenic ability of FaDu-CR cells in nude mice treated with cetuximab, as well as reduced GPX4 and Ki67 levels in tumor tissues. In conclusion, IDH2 regulated glutathione metabolism and contributed to cetuximab resistance in HNSCC. This study explores strategies to ameliorate cetuximab resistance in HNSCC preclinical models, providing new insights for reversing cetuximab resistance in HNSCC.

Keywords:  Cetuximab resistance; Glutathione metabolism; HNSCC; IDH2; Metabolomics; Transcriptomics

DOI:  https://doi.org/10.1016/j.cellsig.2025.111620
Nat Rev Cancer. 2025 Jan 20.

Metabolic interplays between the tumour and the host shape the tumour macroenvironment.

Patricia Altea-Manzano, Amanda Decker-Farrell, Tobias Janowitz, Ayelet Erez.

Metabolic reprogramming of cancer cells and the tumour microenvironment are pivotal characteristics of cancers, and studying these processes offer insights and avenues for cancer diagnostics and therapeutics. Recent advancements have underscored the impact of host systemic features, termed macroenvironment, on facilitating cancer progression. During tumorigenesis, these inherent features of the host, such as germline genetics, immune profile and the metabolic status, influence how the body responds to cancer. In parallel, as cancer grows, it induces systemic effects beyond the primary tumour site and affects the macroenvironment, for example, through inflammation, the metabolic end-stage syndrome of cachexia, and metabolic dysregulation. Therefore, understanding the intricate metabolic interplay between the tumour and the host is a growing frontier in advancing cancer diagnosis and therapy. In this Review, we explore the specific contribution of the metabolic fitness of the host to cancer initiation, progression and response to therapy. We then delineate the complex metabolic crosstalk between the tumour, the microenvironment and the host, which promotes disease progression to metastasis and cachexia. The metabolic relationships among the host, cancer pathogenesis and the consequent responsive systemic manifestations during cancer progression provide new perspectives for mechanistic cancer therapy and improved management of patients with cancer.

DOI: https://doi.org/10.1038/s41568-024-00786-4
Biochemistry. 2025 Jan 22.

Glutamine Synthetase: Diverse Regulation and Functions of an Ancient Enzyme.

Markus C B Tecson, Cyrina Geluz, Yuly Cruz, Eric R Greene.

Glutamine synthetase (GS) is a ubiquitous enzyme central to nitrogen metabolism, catalyzing the ATP-dependent formation of glutamine from glutamate and ammonia. Positioned at the intersection of nitrogen metabolism with carbon metabolism, the activity of GS is subject to sophisticated regulation. While the intricate regulatory pathways that govern Escherichia coli GS were established long ago, recent work has demonstrated that homologues are controlled by multiple distinct regulatory patterns, such as the metabolite induced oligomeric state formation in archaeal GS by 2-oxoglutarate. Such work was enabled in large part by advances in cryo-electron microscopy (cryoEM) that allowed greater structural access to this large enzyme complex, such as assessment of the large heterogeneous oligomeric states of GS and protein-interactor-GS complexes. This perspective highlights recent advances in understanding GS regulation, focusing on the dynamic interplay between its oligomeric state, metabolite binding, and protein interactors. These interactions modulate GS activity, influencing cellular processes such as nitrogen assimilation, carbon metabolism, and stress responses. Furthermore, we explore the emerging concept of GS "moonlighting" functions, revealing its roles in palmitoylation, cell cycle regulation, and ion channel modulation. These diverse functions highlight a newfound versatility of GS beyond its primary catalytic role and suggest complex roles in health and disease that warrant further study.

DOI: https://doi.org/10.1021/acs.biochem.4c00763