bims-glucam 2025-03-30 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–03–30
eleven papers selected by
Sreeparna Banerjee, Middle East Technical University

Metabolism of Tryptophan, Glutamine, and Asparagine in Cancer Immunotherapy-Synergism or Mechanism of Resistance?
The mitochondrial thioredoxin system regulates the TCA cycle-derived metabolic fluxes toward the GS/GOGAT cycle in illuminated leaves.
Fatty Acid Metabolism Provides an Essential Survival Signal in OxPhos and BCR DLBCL Cells.
GPR35 prevents osmotic stress induced cell damage.
The Role of Non-Coding RNAs in MYC-Mediated Metabolic Regulation: Feedback Loops and Interactions.
The glutamine starvation-induced lncRNA FERRIN suppresses ferroptosis via the stabilization of SLC7A11 mRNA.
Metabolism Meets Translation: Dietary and Metabolic Influences on tRNA Modifications and Codon Biased Translation.
Metabolic Adaptations Driving Innate Immune Memory: Mechanisms and Therapeutic Implications.
Macrophages harness hepatocyte glutamate to boost liver regeneration.
ISG15 Enhances the Activity of γ-Glutamate Cysteine Ligase to Suppress Apoptosis in High Fat Diet-Promoted Hepatocellular Carcinoma.
Structural Insights into Amyloid Polymorphism: The Impact of Glutamine to Norleucine Substitutions in GNNQQNY Aggregation.

Metabolites. 2025 Feb 21. pii: 144. [Epub ahead of print]15(3):

Metabolism of Tryptophan, Glutamine, and Asparagine in Cancer Immunotherapy-Synergism or Mechanism of Resistance?

Kajetan Kiełbowski, Estera Bakinowska, Rafał Becht, Andrzej Pawlik.

  Amino acids are crucial components of proteins, key molecules in cellular physiology and homeostasis. However, they are also involved in a variety of other mechanisms, such as energy homeostasis, nitrogen exchange, further synthesis of bioactive compounds, production of nucleotides, or activation of signaling pathways. Moreover, amino acids and their metabolites have immunoregulatory properties, significantly affecting the behavior of immune cells. Immunotherapy is one of the oncological treatment methods that improves cytotoxic properties of one's own immune system. Thus, enzymes catalyzing amino acid metabolism, together with metabolites themselves, can affect immune antitumor properties and responses to immunotherapy. In this review, we will discuss the involvement of tryptophan, glutamine, and asparagine metabolism in the behavior of immune cells targeted by immunotherapy and summarize results of the most recent investigations on the impact of amino acid metabolites on immunotherapy.

Keywords:  amino acid metabolism; asparagine; cancer; glutamine; immunotherapy; tryptophan

DOI:  https://doi.org/10.3390/metabo15030144
J Exp Bot. 2025 Mar 24. pii: eraf125. [Epub ahead of print]

The mitochondrial thioredoxin system regulates the TCA cycle-derived metabolic fluxes toward the GS/GOGAT cycle in illuminated leaves.

Paulo V L Souza, Vicente T C B Alencar, Humaira Bahadar, Joaquim Albenisio G Silveira, Danilo M Daloso.

  Previous studies suggest that the synthesis of glutamate/glutamine is regulated by the mitochondrial thioredoxin (TRX) system. However, the mechanisms behind it remains unclear. Here, we demonstrated that the level of citrate and glutamate was higher in illuminated leaves from Arabidopsis mutants lacking the mitochondrial TRX o1 (trxo1) or both NADPH-dependent TRX reductases A/B (ntrab), that are found in nucleus, cytosol and mitochondria, when compared to the wild type (WT). Increased 13C-labelling in glutamate derived from 13C-pyruvate was observed in illuminated trxo1 and ntrab leaves, but not in WT and in the microsomal trxh2 mutant. The lack of TRX o1 decreased the content and activity of glutamine synthetase (GS), which leads to a lower level of glutamine, and exacerbated the increases in GS activity triggered by high light, when compared to the WT. The level of glutamine was positively correlated with the percentage of the oxidized GS band. However, the GS redox status was unaltered in all mutants. Our results indicate mitochondrial TRX mutants have higher metabolic fluxes from the TCA to the GS/GOGAT cycle in vivo, likely associated to an increased substrate availability and by direct-and-indirect TRX-mediated mechanisms that regulate enzymes of both TCA and GS/GOGAT cycles.

Keywords:  Glutamate; glutamine; high light; redox regulation; thioredoxin reductases

DOI:  https://doi.org/10.1093/jxb/eraf125
Biomedicines. 2025 Mar 13. pii: 707. [Epub ahead of print]13(3):

Fatty Acid Metabolism Provides an Essential Survival Signal in OxPhos and BCR DLBCL Cells.

Aurélie Montagne, Konstantina Kotta, Karoline Kielbassa-Elkadi, Isabelle Martins, José Ángel Martinez-Climent, Guido Kroemer, Catherine Thieblemont, Véronique Baud.

  Backgroung/objectives: Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype of malignant lymphoma and is a heterogeneous disease with various gene and chromosomal abnormalities. The development of novel therapeutic treatments has improved DLBCL prognosis, but patients with early relapse or refractory disease have a poor outcome (with a mortality of around 40%). Metabolic reprogramming is a hallmark of cancer cells. Fatty acid (FA) metabolism is frequently altered in cancer cells and recently emerged as a critical survival path for cancer cell survival. Methods: We first performed the metabolic characterization of an extended panel of DLBCL cell lines, including lipid droplet content. Then, we investigated the effect of drugs targeting FA metabolism on DLBCL cell survival. Further, we studied how the combination of drugs targeting FA and either mitochondrial metabolism or mTOR pathway impacts on DLBCL cell death. Results: Here, we reveal, using a large panel of DLBCL cell lines characterized by their metabolic status, that targeting of FA metabolism induces massive DLBCL cell death regardless of their OxPhos or BCR/glycolytic subtype. Further, FA drives resistance of DLBCL cell death induced by mitochondrial stress upon treatment with either metformin or L-asparaginase, two FDA-approved antimetabolic drugs. Interestingly, combining inhibition of FA metabolism with that of the mTOR oncogenic pathway strongly potentiates DLBCL cell death. Conclusion: Altogether, our data highlight the central role played by FA metabolism in DLBCL cell survival, independently of their metabolic subtype, and provide the framework for the use of drugs targeting this metabolic vulnerability to overcome resistance in DLBCL patients.

Keywords:  B-cell lymphoma; DLBCL; fatty acid; metabolism; mitochondrial stress; survival

DOI:  https://doi.org/10.3390/biomedicines13030707
Commun Biol. 2025 Mar 22. 8(1): 478

GPR35 prevents osmotic stress induced cell damage.

Joshua E Elias, Mekdes Debela, Gavin W Sewell, Richard J Stopforth, Hannah Partl, Sophie Heissbauer, Lorraine M Holland, Tom H Karlsen, Arthur Kaser, Nicole C Kaneider.

GPR35 is an orphan G-protein coupled receptor that has been implicated in the development of cancer. GPR35 regulates the Na+/K+-ATPase's pump and signalling function. Here we show GPR35's critical role in ion flux that in turn controls cellular osmotic pressure and Na+-dependent transport in HepG2 and SW480 cells. GPR35 deficiency results in increased levels of intracellular Na+, osmotic stress and changes in osmolytes leading to increased cells size and decreased glutamine import in vitro and in vivo. The GPR35-T108M risk variant, which increases risk for primary sclerosing cholangitis and inflammatory bowel disease, leads to lower intracellular Na+ levels, and enhanced glutamine uptake. High salt diet (HSD) in wildtype mice resembles the intestinal epithelial phenotype of their Gpr35-/- littermates with decreased Goblet cell size and numbers. This indicates that GPR35's regulation of the Na+/K+-ATPase controls ion homeostasis, osmosis and Na+-dependent transporters.

DOI: https://doi.org/10.1038/s42003-025-07848-9
Noncoding RNA. 2025 Mar 18. pii: 27. [Epub ahead of print]11(2):

The Role of Non-Coding RNAs in MYC-Mediated Metabolic Regulation: Feedback Loops and Interactions.

Aliaa Amr Alamoudi.

  Metabolic reprogramming is a hallmark of cancer, crucial for supporting the rapid energy demands of tumor cells. MYC, often deregulated and overexpressed, is a key driver of this shift, promoting the Warburg effect by enhancing glycolysis. However, there remains a gap in understanding the mechanisms and factors influencing MYC's metabolic roles. Recently, non-coding RNAs (ncRNAs) have emerged as important modulators of MYC functions. This review focuses on ncRNAs that regulate MYC-driven metabolism, particularly the Warburg effect. The review categorizes these ncRNAs into three main groups based on their interaction with MYC and examines the mechanisms behind these interactions. Additionally, we explore how different types of ncRNAs may collaborate or influence each other's roles in MYC regulation and metabolic function, aiming to identify biomarkers and synthetic lethality targets to disrupt MYC-driven metabolic reprogramming in cancer. Finaly, the review highlights the clinical implications of these ncRNAs, providing an up-to-date summary of their potential roles in cancer prognosis and therapy. With the recent advances in MYC-targeted therapy reaching clinical trials, the exciting potential of combining these therapies with ncRNA-based strategies holds great promise for enhancing treatment efficacy.

Keywords:  MYC; Warburg-effect; circular RNA; glycolysis; long non-coding RNA; microRNA; non-coding RNA; tumor-metabolism

DOI:  https://doi.org/10.3390/ncrna11020027
Int J Biol Macromol. 2025 Mar 22. pii: S0141-8130(25)02940-X. [Epub ahead of print]308(Pt 1): 142388

The glutamine starvation-induced lncRNA FERRIN suppresses ferroptosis via the stabilization of SLC7A11 mRNA.

Kaiyue Liu, Zhongyu Wang, Xiaorui Guo, Jingjing Luo, Xianning Wu, Fang Wang, Yide Mei.

  As an essential nutrient for cancer cell survival, glutamine plays both promoting and inhibitory roles in ferroptosis; however, the underlying mechanisms remain obscure. Emerging evidence suggests that long noncoding RNAs (lncRNAs) are crucial regulators of ferroptosis. Nevertheless, it remains unclear whether lncRNAs are involved in glutamine-regulated ferroptosis. In this study, we report that the lncRNA FERRIN is induced by the transcription factor ATF4 under glutamine starvation conditions. FERRIN functions as an inhibitor of ferroptosis by upregulating SLC7A11 expression. Mechanistically, FERRIN interacts with the RNA binding protein hnRNPK, facilitating its binding to SLC7A11 mRNA and leading to the stabilization of SLC7A11 mRNA. Consistent with its inhibitory role in ferroptosis, FERRIN promotes in vitro cancer cell proliferation and in vivo xenograft tumor growth through its modulation of SLC7A11. Collectively, these findings establish FERRIN as a critical negative regulator of ferroptosis and suggest that FERRIN may represent an important link between glutamine availability and ferroptosis.

Keywords:  FERRIN; Ferroptosis; Glutamine starvation; SLC7A11

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.142388
Wiley Interdiscip Rev RNA. 2025 Mar-Apr;16(2):16(2): e70011

Metabolism Meets Translation: Dietary and Metabolic Influences on tRNA Modifications and Codon Biased Translation.

Sherif Rashad, Aseel Marahleh.

  Transfer RNA (tRNA) is not merely a passive carrier of amino acids, but an active regulator of mRNA translation controlling codon bias and optimality. The synthesis of various tRNA modifications is regulated by many "writer" enzymes, which utilize substrates from metabolic pathways or dietary sources. Metabolic and bioenergetic pathways, such as one-carbon (1C) metabolism and the tricarboxylic acid (TCA) cycle produce essential substrates for tRNA modifications synthesis, such as S-Adenosyl methionine (SAM), sulfur species, and α-ketoglutarate (α-KG). The activity of these metabolic pathways can directly impact codon decoding and translation via regulating tRNA modifications levels. In this review, we discuss the complex interactions between diet, metabolism, tRNA modifications, and mRNA translation. We discuss how nutrient availability, bioenergetics, and intermediates of metabolic pathways, modulate the tRNA modification landscape to fine-tune protein synthesis. Moreover, we highlight how dysregulation of these metabolic-tRNA interactions contributes to disease pathogenesis, including cancer, metabolic disorders, and neurodegenerative diseases. We also discuss the new emerging field of GlycoRNA biology drawing parallels from glycobiology and metabolic diseases to guide future directions in this area. Throughout our discussion, we highlight the links between specific modifications, their metabolic/dietary precursors, and various diseases, emphasizing the importance of a metabolism-centric tRNA view in understanding many pathologies. Future research should focus on uncovering the interplay between metabolism and tRNA in specific cellular and disease contexts. Addressing these gaps will guide new research into novel disease interventions.

Keywords:  codon; epitranscriptome; mRNA translation; metabolism; tRNA modifications

DOI:  https://doi.org/10.1002/wrna.70011
J Leukoc Biol. 2025 Mar 26. pii: qiaf037. [Epub ahead of print]

Metabolic Adaptations Driving Innate Immune Memory: Mechanisms and Therapeutic Implications.

Dan Hao, Margaret A McBride, Julia K Bohannon, Antonio Hernandez, Benjamin Klein, David L Williams, Edward R Sherwood.

  Immune memory is a hallmark of the adaptive immune system. However, recent research reveals that innate immune cells also retain memory of prior pathogen exposure that prompts enhanced responses to subsequent infections. This phenomenon is termed "innate immune memory" or "trained immunity." Notably, remodeling of cellular metabolism, which closely links to epigenetic reprogramming, is a prominent feature of innate immune memory. Adaptations in glycolysis, the tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), glutaminolysis, and lipid synthesis pathways are critical for establishing innate immune memory. This review provides an overview of the current understanding of how metabolic adaptations drive innate immune memory. This understanding is fundamental to understanding innate immune system functions and advancing therapies against infectious diseases.

Keywords:  Innate immune memory; immune therapy; metabolism; trained immunity

DOI:  https://doi.org/10.1093/jleuko/qiaf037
Nature. 2025 Mar 26.

Macrophages harness hepatocyte glutamate to boost liver regeneration.

María Del Mar Rigual, Mariana Angulo-Aguado, Sladjana Zagorac, Ruth Álvarez-Díaz, Marta Benítez-Mondéjar, Fengming Yi, Carlos Martínez-Garay, Karla Santos-de-Frutos, Eunjeong Kim, Ramón Campos-Olivas, Nabil Djouder.

Liver regeneration after hepatectomy follows accurate coordination with the body's specific requirements1-3. However, the molecular mechanisms, factors and particular hepatocyte population influencing its efficiency remain unclear. Here we report on a unique regeneration mechanism involving unconventional RPB5 prefoldin interactor 1 (URI1), which exclusively colocalizes with, binds to and activates glutamine synthase (GS) in pericentral hepatocytes. Genetic GS or URI1 depletion in mouse pericentral hepatocytes increases circulating glutamate levels, accelerating liver regeneration after two-third hepatectomy. Conversely, mouse hepatocytic URI1 overexpression hinders liver restoration, which can be reversed by elevating glutamate through supplementation or genetic GS depletion. Glutamate metabolically reprograms bone-marrow-derived macrophages, stabilizing HIF1α, which transcriptionally activates WNT3 to promote YAP1-dependent hepatocyte proliferation, boosting liver regeneration. GS regulation by URI1 is a mechanism that maintains optimal glutamate levels, probably to spatiotemporally fine-tune liver growth in accordance with the body's homeostasis and nutrient supply. Accordingly, in acute and chronic injury models, including in cirrhotic mice with low glutamate levels and in early mortality after liver resection, as well as in mice undergoing 90% hepatectomy, glutamate addition enhances hepatocyte proliferation and survival. Furthermore, URI1 and GS expression co-localize in human hepatocytes and correlate with WNT3 in immune cells across liver disease stages. Glutamate supplementation may therefore support liver regeneration, benefiting patients awaiting transplants or recovering from hepatectomy.

DOI: https://doi.org/10.1038/s41586-025-08778-6
Adv Sci (Weinh). 2025 Mar 24. e2416401

ISG15 Enhances the Activity of γ-Glutamate Cysteine Ligase to Suppress Apoptosis in High Fat Diet-Promoted Hepatocellular Carcinoma.

Xinran Liu, Qiujin Ma, Zhao Jia, Yihao Zhou, Churong Zou, Yushuo Xiao, Yuchen Chen, Chuyao Ma, Liangliang Song, Jing Yang, Chen Wang, Huidie Xu, Hong Chen, Jiajian Shi, Junqiu Yue, Yu Sun, Desheng Hu, Robert B Petersen, Yangkai Li, Anlin Peng, Kun Huang, Ling Zheng.

  Obesity is a leading risk factor for development of hepatocellular carcinoma (HCC). High-fat intake produces cytotoxic effects in liver cells, such as excessive reactive oxygen species (ROS) accumulation and apoptosis. How HCC cells regulate ROS level and escape the cytotoxic effects of high fat diet (HFD) stress remains unclear. Herein, this work reports a critical anti-ROS/apoptotic role of the ubiquitin-like protein interferon stimulated gene 15 (ISG15) in HFD-promoted HCC. In mouse models and clinical HCC samples, upregulation of ISG15 is associated with hepatic steatosis. Notably, upregulated ISG15 elevates cellular glutathione levels, which subsequently reduces ROS accumulation and confers resistance to apoptosis in HCC cells. In diethylnitrosamine-induced HCC mouse model, HFD-feeding promotes HCC progression in wildtype mice, while tumor growth is significantly suppressed accompanied by apoptosis of HCC cells in Isg15-KO mice. Mechanistically, ISG15 promotes the activity of γ-glutamate cysteine ligase (γ-GCL), a rate-limiting heterodimeric holoenzyme of glutathione synthesis consisting of glutamate-cysteine ligase catalytic subunit (GCLC) and glutamate-cysteine ligase modifier subunit (GCLM). Independent of ISGylation, ISG15 forms an ISG15/GCLM/GCLC complex that promotes GCLM-GCLC interaction, increases glutathione generation and inhibits HFD-induced apoptosis in HCC cells. Together, an anti-apoptotic ISG15-γ-GCL-glutothione axis is suggested in HFD-promoted HCC.

Keywords:  glutathione; hepatocellular carcinoma; high fat diet; interferon stimulated gene 15; reactive oxygen species; γ‐glutamate cysteine ligase

DOI:  https://doi.org/10.1002/advs.202416401
Chemistry. 2025 Mar 28. e202404255

Structural Insights into Amyloid Polymorphism: The Impact of Glutamine to Norleucine Substitutions in GNNQQNY Aggregation.

Fruzsina Bencs, Loránd Románszki, Viktor Farkas, András Perczel.

  Polypeptides can self-assemble into highly organized amyloid structures through complex and poorly understood mechanisms. To better understand the key parameters governing amyloidogenesis, we investigated the aggregation of the Sup35 prion-derived GNNQQNY sequence alongside two rationally designed mutants, glutamine to norleucine in position 4th or 5th, where selective removal of hydrogen bonding capacity reduces amyloid structural stability. Our findings reveal that β-sheet arrays form rapidly as an initial step, followed by π-π aromatic interactions between Tyr residues, which drive hierarchical self-assembly into 3D fibrillar structures via hydrophobic zippers and partial water exclusion. As the oligomers grow, they also acquire twist and chirality at the protofilament level, with Tyr ladders serving as key interaction surfaces that dictate the final amyloid architecture. These ladders guide protofibrils to assemble into either oppositely twisted chiral fibers or achiral nanocrystals, contributing to amyloid polymorphism. The emergence of distinct polymorphs is influenced by multiple factors, including fibril twisting, side-chain interactions, solvent exclusion, and local microenvironmental conditions. Our study provides crucial insights into the hierarchical nature of amyloid self-assembly and highlights the structural adaptability of amyloid fibrils, which is essential for designing functional amyloids and understanding the pathogenicity of disease-associated aggregates.

Keywords:  Amyloid polymorphism; Sup35 GNNQQNY peptide; chiroptical spectroscopy; hydrophobic core stabilization; β-sheet self-assembly

DOI:  https://doi.org/10.1002/chem.202404255