bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2024–12–29
eight papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. GLS1-mediated glutamine metabolism mitigates oxidative stress-induced matrix degradation, ferroptosis, and senescence in nucleus pulposus cells by modulating Fe2+ homeostasis.
  2. Deciphering Colorectal Cancer-Hepatocyte Interactions: A Multiomic Platform for Interrogation of Metabolic Crosstalk in the Liver-Tumor Microenvironment.
  3. Genome-scale modeling identifies dynamic metabolic vulnerabilities during the epithelial to mesenchymal transition.
  4. Oncometabolites in pancreatic cancer: Strategies and its implications.
  5. Restoring Mitochondrial Quantity and Quality to Reverse Warburg Effect and Drive Tumor Differentiation.
  6. Nanozyme-mediated glutathione depletion for enhanced ROS-based cancer therapies: a comprehensive review.
  7. Cysteine Import via the High Affinity Glutathione Transporter Hgt1 Rescues Glutathione Auxotrophy in Yeast.
  8. Optimized MALDI2-Mass Spectrometry Imaging for Stable Isotope Tracing of Tissue-Specific Metabolic Pathways in Mice.
  1. Free Radic Biol Med. 2024 Dec 20. pii: S0891-5849(24)01152-3. [Epub ahead of print]
    GLS1-mediated glutamine metabolism mitigates oxidative stress-induced matrix degradation, ferroptosis, and senescence in nucleus pulposus cells by modulating Fe2+ homeostasis.
    Jiajun Wu, Tianyu Qin, Weitao Han, Chao Zhang, Xiaohe Zhang, Zhengqi Huang, Yuliang Wu, Yichun Xu, Kang Xu, Wei Ye.
      Intervertebral disc degeneration (IDD) is intricately linked to the pathogenesis of low back pain (LBP). The balance of nucleus pulposus (NP) cell and intervertebral disc (IVD) integrity is significantly supported by amino acid metabolism within an avascular milieu. However, the specific metabolic demands during the progression of IDD are not fully understood. Our study revealed that GLS1, a key enzyme that regulates glutamine metabolism, is key for mitigating NP cell ferroptosis, senescence, and IDD progression. Our findings show that GLS1 overexpression modulates glutamine metabolism, reducing NP cell matrix degradation, ferroptosis, and senescence. Mechanistically, GLS1 interacts with NFS1 and regulates ferrous ion (Fe2+) homeostasis. GLS1-driven glutamine metabolism facilitates acetyl-CoA production, which is important for the histone acetylation of NFS1. Thus, restoring GLS1 activity through gene overexpression to maintain Fe2+ homeostasis is a promising approach for mitigating matrix degradation, ferroptosis, and senescence and for rejuvenating intervertebral discs. Collectively, our data suggest a model in which GLS1-mediated glutamine metabolism is associated with NP cell matrix degradation, ferroptosis, and senescence and that NFS1 can be targeted to maintain Fe2+ homeostasis and ultimately revitalize intervertebral discs.
    Keywords:  Ferroptosis; GLS1; Glutamine metabolism; Intervertebral disc degeneration; Oxidative stress; Senescence
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.12.043
  2. bioRxiv. 2024 Dec 14. pii: 2024.12.06.627264. [Epub ahead of print]
    Deciphering Colorectal Cancer-Hepatocyte Interactions: A Multiomic Platform for Interrogation of Metabolic Crosstalk in the Liver-Tumor Microenvironment.
    Alisa B Nelson, Lyndsay E Reese, Elizabeth Rono, Eric D Queathem, Yinjie Qiu, Braedan M McCluskey, Alexandra Crampton, Eric Conniff, Katherine Cummins, Ella Boytim, Senali Dansou, Justin Hwang, Sandra Safo, Patrycja Puchalska, David K Wood, Kathryn L Schwertfeger, Peter A Crawford.
      Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to adapt to and exploit their microenvironment for sustained growth. The liver is a common site of metastasis, but the interactions between tumor cells and hepatocytes remain poorly understood. In the context of liver metastasis, these interactions play a crucial role in promoting tumor survival and progression. This study leverages multiomics coverage of the microenvironment via liquid chromatography and high-resolution, high-mass accuracy mass spectrometry-based untargeted metabolomics, 13 C-stable isotope tracing, and RNA sequencing to uncover the metabolic impact of co-localized primary hepatocytes and a colon adenocarcinoma cell line, SW480, using a 2D co-culture model. Metabolic profiling revealed disrupted Warburg metabolism with an 80% decrease in glucose consumption and 94% decrease in lactate production by hepatocyte-SW480 co-cultures relative to SW480 control cultures. Decreased glucose consumption was coupled with alterations in glutamine and ketone body metabolism, suggesting a possible fuel switch upon co-culturing. Further, integrated multiomic analysis indicates that disruptions in metabolic pathways, including nucleoside biosynthesis, amino acids, and TCA cycle, correlate with altered SW480 transcriptional profiles and highlight the importance of redox homeostasis in tumor adaptation. Finally, these findings were replicated in 3-dimensional microtissue organoids. Taken together, these studies support a bioinformatic approach to study metabolic crosstalk and discovery of potential therapeutic targets in preclinical models of the tumor microenvironment.
    DOI:  https://doi.org/10.1101/2024.12.06.627264
  3. Commun Biol. 2024 Dec 27. 7(1): 1704
    Genome-scale modeling identifies dynamic metabolic vulnerabilities during the epithelial to mesenchymal transition.
    Rupa Bhowmick, Scott Campit, Shiva Krishna Katkam, Venkateshwar G Keshamouni, Sriram Chandrasekaran.
      Epithelial-to-mesenchymal transition (EMT) is a conserved cellular process critical for embryogenesis, wound healing, and cancer metastasis. During EMT, cells undergo large-scale metabolic reprogramming that supports multiple functional phenotypes including migration, invasion, survival, chemo-resistance and stemness. However, the extent of metabolic network rewiring during EMT is unclear. In this work, using genome-scale metabolic modeling, we perform a meta-analysis of time-course transcriptomics, time-course proteomics, and single-cell transcriptomics EMT datasets from cell culture models stimulated with TGF-β. We uncovered temporal metabolic dependencies in glycolysis and glutamine metabolism, and experimentally validated isoform-specific dependency on Enolase3 for cell survival during EMT. We derived a prioritized list of metabolic dependencies based on model predictions, literature mining, and CRISPR-Cas9 essentiality screens. Notably, enolase and triose phosphate isomerase reaction fluxes significantly correlate with survival of lung adenocarcinoma patients. Our study illustrates how integration of heterogeneous datasets using a mechanistic computational model can uncover temporal and cell-state-specific metabolic dependencies.
    DOI:  https://doi.org/10.1038/s42003-024-07408-7
  4. World J Exp Med. 2024 Dec 20. 14(4): 96005
    Oncometabolites in pancreatic cancer: Strategies and its implications.
    Arunima Maiti, Susmita Mondal, Sounetra Choudhury, Arnab Bandopadhyay, Sanghamitra Mukherjee, Nilabja Sikdar.
      Pancreatic cancer (PanCa) is a catastrophic disease, being third lethal in both the genders around the globe. The possible reasons are extreme disease invasiveness, highly fibrotic and desmoplastic stroma, dearth of confirmatory diagnostic approaches and resistance to chemotherapeutics. This inimitable tumor microenvironment (TME) or desmoplasia with excessive extracellular matrix accumulation, create an extremely hypovascular, hypoxic and nutrient-deficient zone inside the tumor. To survive, grow and proliferate in such tough TME, pancreatic tumor and stromal cells transform their metabolism. Transformed glucose, glutamine, fat, nucleotide metabolism and inter-metabolite communication between tumor and TME in synergism, impart therapy resistance, and immunosuppression in PanCa. Thus, a finer knowledge of altered metabolism would uncover its metabolic susceptibilities. These unique metabolic targets may help to device novel diagnostic/prognostic markers and therapeutic strategies for better management of PanCa. In this review, we sum up reshaped metabolic pathways in PanCa to formulate detection and remedial strategies of this devastating disease.
    Keywords:  Anti-pancreatic cancer therapy; Metabolic reprogramming; Metabolic symbiosis; Pancreatic cancer; Therapy resistance
    DOI:  https://doi.org/10.5493/wjem.v14.i4.96005
  5. Res Sq. 2024 Dec 13. pii: rs.3.rs-5494402. [Epub ahead of print]
    Restoring Mitochondrial Quantity and Quality to Reverse Warburg Effect and Drive Tumor Differentiation.
    Jiangbin Ye, Haowen Jiang, Sarah Tiche, Clifford He, Junyan Liu, Fuyun Bian, Mohamed Jedoui, Balint Forgo, Md Tauhidul Islam, Meng Zhao, Pamela Emengo, Bo He, Yang Li, Albert Li, Anh Truong, Jestine Ho, Cathyrin Simmermaker, Yanan Yang, Meng-Ning Zhou, Zhen Hu, Katrin Svensson, Daniel Cuthbertson, Florette Hazard, Lei Xing, Hiroyuki Shimada, Bill Chiu.
      Reduced mitochondrial quality and quantity in tumors is associated with dedifferentiation and increased malignancy. However, it remains unclear how to restore mitochondrial quantity and quality in tumors, and whether mitochondrial restoration can drive tumor differentiation. Our study shows that restoring mitochondrial function using retinoic acid (RA) to boost mitochondrial biogenesis and a mitochondrial uncoupler to enhance respiration synergistically drives neuroblastoma differentiation and inhibits proliferation. U-13C-glucose/glutamine isotope tracing revealed a metabolic shift from the pentose phosphate pathway to oxidative phosphorylation, accelerating the TCA cycle and switching substrate preference from glutamine to glucose. These effects were reversed by ETC inhibitors or in ρ0 cells lacking mtDNA, emphasizing the necessity of mitochondrial function for differentiation. Dietary RA and uncoupler treatment promoted tumor differentiation in an orthotopic neuroblastoma xenograft model, evidenced by neuropil production and Schwann cell recruitment. Single-cell RNA sequencing analysis of the orthotopic xenografts revealed that this strategy effectively eliminated the stem cell population, promoted differentiation, and increased mitochondrial gene signatures along the differentiation trajectory, which could potentially significantly improve patient outcomes. Collectively, our findings establish a mitochondria-centric therapeutic strategy for inducing tumor differentiation, suggesting that maintaining/driving differentiation in tumor requires not only ATP production but also continuous ATP consumption and sustained ETC activity.
    DOI:  https://doi.org/10.21203/rs.3.rs-5494402/v1
  6. Nanomedicine (Lond). 2024 Dec 27. 1-12
    Nanozyme-mediated glutathione depletion for enhanced ROS-based cancer therapies: a comprehensive review.
    Xinyu Wang, Nan Wei, Yang Zhang, Yuan Fang, Yijun Li, Songguo Li, Zhanggui Wang, Chenglong Sun.
      Nanozymes can improve reactive oxygen species (ROS)-based cancer therapies by targeting cancer cells' antioxidant defense mechanisms, particularly glutathione (GSH) depletion, to overcome ROS-resistant cancer cells. Nanozymes, innovative enzyme-mimetic nanomaterials, can generate ROS, alter the tumor microenvironment (TME), and synergize with photodynamic therapy (PDT), chemodynamic therapy (CDT), radiotherapy, and immunotherapy. This review shows how nanozymes catalyze ROS generation, selectively deplete GSH, and target cancer elimination, offering clear advantages over standard therapies. Nanozymes selectively target cancer cells' antioxidant defenses to improve PDT, CDT, and radiation therapies. To maximize nanozyme-based cancer treatment efficacy, biodistribution, biocompatibility, and tumor heterogeneity must be assessed. To improve cancer treatment, multifunctional, stimuli-responsive nanozymes and synergistic combination drugs should be developed.
    Keywords:  Nanozymes; multimodal cancer therapies; nanozymes glutathione depletion; reactive oxygen species (ROS); tumor microenvironment (TME)
    DOI:  https://doi.org/10.1080/17435889.2024.2446138
  7. J Biol Chem. 2024 Dec 21. pii: S0021-9258(24)02633-4. [Epub ahead of print] 108131
    Cysteine Import via the High Affinity Glutathione Transporter Hgt1 Rescues Glutathione Auxotrophy in Yeast.
    Crystal C McGee, Tirthankar Bandyopadhyay, Cailin N McCracken, Evan Talib, Courtney E Patterson, Caryn E Outten.
      Glutathione (GSH) is an abundant thiol-containing tripeptide that functions in redox homeostasis, protein folding, and iron metabolism. In Saccharomyces cerevisiae, GSH depletion leads to increased sensitivity to oxidants and other toxic compounds, disruption of Fe-S cluster biogenesis, and eventually cell death. GSH pools are supplied by intracellular biosynthesis and GSH import from the extracellular environment. Consequently, in GSH-depleted growth media, deletion of the gene encoding the first enzyme in the GSH biosynthetic pathway (GSH1), is lethal in yeast. At the other extreme, GSH overaccumulation via overexpression of the high affinity GSH transporter Hgt1 is also toxic to cells, leading to reductive stress. Here we engineered a yeast strain that combines GSH1 deletion with HGT1 overexpression to study the cellular effects of oscillating between GSH deplete and replete conditions. Surprisingly, we find that constitutive expression of HGT1 in gsh1Δ cells rescues the GSH auxotrophy of this strain. We also show that addition of cysteine or cysteine derivatives to the growth media is required for this rescue. GSH limitation in yeast causes intracellular iron overload due to disruption of an iron-sulfur (Fe-S) cluster dependent pathway that regulates the activity of the low iron sensing transcription factors Aft1 and Aft2. Analysis of iron regulation and other Fe-S cluster dependent pathways reveals that HGT1 overexpression partially alleviates the iron starvation-like response of gsh1Δ cells. Taken together, these results suggest that HGT1 overexpression facilitates import of cysteine or cysteine derivatives that allow limited Fe-S cluster biogenesis to sustain cell growth in the absence of GSH.
    Keywords:  Saccharomyces cerevisiae; amino acid transport; cysteine; glutathione; iron metabolism; iron-sulfur protein; metal homeostasis; redox regulation; yeast genetics
    DOI:  https://doi.org/10.1016/j.jbc.2024.108131
  8. Anal Chem. 2024 Dec 27.
    Optimized MALDI2-Mass Spectrometry Imaging for Stable Isotope Tracing of Tissue-Specific Metabolic Pathways in Mice.
    Yanyan Chen, Yuanyuan Song, Zhu Yang, Yi Ru, Peisi Xie, Jing Han, Xuyang Chai, Jianing Wang, Zongwei Cai.
      Spatial stable isotope tracing metabolic imaging is a cutting-edge technique designed to investigate tissue-specific metabolic functions and heterogeneity. Traditional matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) techniques often struggle with low coverage of low-molecular-weight (LMW) metabolites, which are often crucial for spatial metabolic studies. To address this, we developed a high-coverage spatial isotope tracing metabolic method that incorporates optimized matrix selection, sample preparation protocols, and enhanced post-ionization (MALDI2) techniques. We employed this approach to mouse kidney, brain, and breast tumors to visualize the spatial dynamics of metabolic flow. Our results revealed diverse regional distributions of nine labeled intermediates derived from 13C6-glucose across glycolysis, glycogen metabolism, and the tricarboxylic acid (TCA) cycle in kidney tissues. In brain sections, we successfully mapped six intermediates from the TCA cycle and glutamate-glutamine (Glu-Gln) cycle simultaneously in distinct neurological regions. Furthermore, in breast cancer tumor tissues, our approach facilitated the mapping of nine metabolic intermediates in multiple pathways, including glycolysis, the pentose phosphate pathway (PPP), and the TCA cycle, illustrating metabolic heterogeneity within the tumor microenvironment. This methodology enhances metabolite coverage, enabling more comprehensive imaging of isotope-labeled metabolites and opening new avenues for exploring the metabolic landscape in various biological contexts.
    DOI:  https://doi.org/10.1021/acs.analchem.4c04600
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