bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2024–09–22
nineteen papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. Glutaminase 2 as a therapeutic target in glioblastoma.
  2. Altered metabolism in cancer: insights into energy pathways and therapeutic targets.
  3. Understanding the Warburg Effect in Cancer.
  4. KDM4A promotes malignant progression of breast cancer by down-regulating BMP9 inducing consequent enhancement of glutamine metabolism.
  5. Advancements in Targeted Therapeutics: Integrating Metabolic Modulation, Immune Engineering, and Biologic Formulation Technologies.
  6. Technologies for Decoding Cancer Metabolism with Spatial Resolution.
  7. Metabolic ripple effects - deciphering how lipid metabolism in cancer interfaces with the tumor microenvironment.
  8. Novel strategies of glutathione depletion in photodynamic and chemodynamic therapy: A review.
  9. Nutrient Levels and Nutrient Sources in Pancreatic Tumors.
  10. An immunotherapeutic hydrogel booster inhibits tumor recurrence and promotes wound healing for postoperative management of melanoma.
  11. Cancer Metabolism: Aspirations for the Coming Decade.
  12. Metabolism and epigenetics: drivers of tumor cell plasticity and treatment outcomes.
  13. Glutamine metabolism-related genes predict the prognostic risk of acute myeloid leukemia and stratify patients by subtype analysis.
  14. Glutaminase inhibition in combination with azacytidine in myelodysplastic syndromes: a phase 1b/2 clinical trial and correlative analyses.
  15. Role of Glutathione in Parkinson's Disease Pathophysiology and Therapeutic Potential of Polyphenols.
  16. Bidirectional dysregulation of synaptic glutamate signaling after transient metabolic failure.
  17. Metabolic regulation of the tumour and its microenvironment: The role of Epstein-Barr virus.
  18. Spatiotemporal metabolomic approaches to the cancer-immunity panorama: a methodological perspective.
  19. Macroautophagy/autophagy promotes resistance to KRASG12D-targeted therapy through glutathione synthesis.
  1. Biochim Biophys Acta Rev Cancer. 2024 Sep 16. pii: S0304-419X(24)00113-6. [Epub ahead of print]1879(6): 189182
    Glutaminase 2 as a therapeutic target in glioblastoma.
    Rithvik K Veeramachaneni, Robert K Suter, Emma Rowland, Anna Jermakowicz, Nagi G Ayad.
      Glioblastoma (GBM) is the most common malignant primary adult brain tumor. Despite standard-of-care treatment, which consists of surgical resection, temozolomide (TMZ) treatment, and radiotherapy, the prognosis for GBM patients remains poor with a five-year survival rate of 5 %. With treatment, the median survival time is 14 months, suggesting the dire need for new, more effective therapies. Glutaminolysis, the metabolic pathway by which cells can convert glutamine to ATP, is essential for the survival of GBM cells and represents a putative target for treatment. Glutamine replenishes tricarboxylic acid (TCA) cycle intermediates through glutaminolysis. The first step of glutaminolysis, the deamination of glutamine, can be carried out by either glutaminase 1 (GLS) or glutaminase 2 (GLS2). However, it is becoming increasingly clear that these enzymes have opposing functions in GBM; GLS induces deamination of glutamine, thereby acting in an oncogenic fashion, while GLS2 has non-enzymatic, tumor-suppressive functions that are repressed in GBM. In this review, we explore the important role of glutaminolysis and the opposing roles of GLS and GLS2 in GBM. Further, we provide a detailed discussion of GLS2's newly discovered non-enzymatic functions that can be targeted in GBM. We conclude by considering therapeutic approaches that have emerged from the understanding of GLS and GLS2's opposing roles in GBM.
    Keywords:  Glioblastoma; Glutaminase; Glutaminolysis; Tumor suppression; Warburg effect
    DOI:  https://doi.org/10.1016/j.bbcan.2024.189182
  2. Mol Cancer. 2024 Sep 18. 23(1): 203
    Altered metabolism in cancer: insights into energy pathways and therapeutic targets.
    Muhammad Tufail, Can-Hua Jiang, Ning Li.
      Cancer cells undergo significant metabolic reprogramming to support their rapid growth and survival. This study examines important metabolic pathways like glycolysis, oxidative phosphorylation, glutaminolysis, and lipid metabolism, focusing on how they are regulated and their contributions to the development of tumors. The interplay between oncogenes, tumor suppressors, epigenetic modifications, and the tumor microenvironment in modulating these pathways is examined. Furthermore, we discuss the therapeutic potential of targeting cancer metabolism, presenting inhibitors of glycolysis, glutaminolysis, the TCA cycle, fatty acid oxidation, LDH, and glucose transport, alongside emerging strategies targeting oxidative phosphorylation and lipid synthesis. Despite the promise, challenges such as metabolic plasticity and the need for combination therapies and robust biomarkers persist, underscoring the necessity for continued research in this dynamic field.
    Keywords:  Cancer metabolism; Glutaminolysis; Glycolysis; Lipid metabolism; Oxidative phosphorylation
    DOI:  https://doi.org/10.1186/s12943-024-02119-3
  3. Cold Spring Harb Perspect Med. 2024 Sep 16. pii: a041532. [Epub ahead of print]
    Understanding the Warburg Effect in Cancer.
    Zhaoqi Li, Muhammad Bin Munim, Daniel A Sharygin, Brooke J Bevis, Matthew G Vander Heiden.
      Rapidly proliferating cells, including cancer cells, adapt metabolism to meet the increased energetic and biosynthetic demands of cell growth and division. Many rapidly proliferating cells exhibit increased glucose consumption and fermentation regardless of oxygen availability, a phenotype termed aerobic glycolysis or the Warburg effect in cancer. Several explanations for why cells engage in aerobic glycolysis and how it supports proliferation have been proposed, but none can fully explain all conditions and data where aerobic glycolysis is observed. Nevertheless, there is convincing evidence that the Warburg effect is important for the proliferation of many cancers, and that inhibiting either glucose uptake or fermentation can impair tumor growth. Here, we discuss what is known about metabolism associated with aerobic glycolysis and the evidence supporting various explanations for why aerobic glycolysis may be important in cancer and other contexts.
    DOI:  https://doi.org/10.1101/cshperspect.a041532
  4. Cancer Cell Int. 2024 Sep 19. 24(1): 322
    KDM4A promotes malignant progression of breast cancer by down-regulating BMP9 inducing consequent enhancement of glutamine metabolism.
    Yuanxiang Chen, Shiyu Yang, Tao Yu, Tao Zeng, Lan Wei, Yiqing You, Jiafeng Tang, Tingting Dang, Haoli Sun, Yan Zhang.
       BACKGROUND: Recent studies have found that histone-modified genes play an increasingly important role in tumor progression. Lysine(K) specific demethylase 4A (KDM4A) is a histone lysine-specific demethylase highly expressed in a variety of malignant tumors, data showed that KDM4A was negatively correlated with the Bone Morphogenetic Protein 9 (BMP9) in breast cancer. And previous experiments have demonstrated that exogenous BMP9 significantly inhibits breast cancer development.
    MATERIALS AND METHODS: We detected the expression of KDM4A in breast cancer and the relationship between KDM4A and BMP9 using real-time quantitative PCR (RT-qPCR) and Western blot, and verified the interaction between KDM4A and BMP9 by ChIP experiments. At the same time, we also detected whether KDM4A had effects on the RNA and protein stability of BMP9 using actinomycin D and cycloheximide. Measurement of alpha-ketoglutarate (α-KG) level by ELISA to observe the effect of BMP9 on glutamine metabolism in breast cancer cells. Nucleoplasmic distribution of KDM4A after exogenous BMP9 treatment in breast cancer cells were observed by immunofluorescence staining and Western blot. A subcutaneous xenograft tumor model in nude mice was used to study the therapeutic effects of exogenous BMP9 and KDM4A inhibitor (JIB-04) in breast cancer. CCK-8, conoly formation, Transwell, wound healing, and immunohistochemistry were used to monitor the growth of tumor and cell function.
    RESULTS: We found that KDM4A was abnormally highly expressed in breast cancer, and silenced BMP9 expression by removing histone methyl groups from the BMP9 gene region. Meanwhile, KDM4A could also reduce the stability of BMP9 protein. BMP9 inhibit glutamine metabolism in breast cancer, resulting in a decrease in its product α-KG, is confirmed by ELISA. Altered nucleoplasmic distribution of KDM4A due to decreased α-KG was confirmed by immunofluorescence staining and Western blot. Animal experiments confirm that the combination of exogenous BMP9 and JIB-04 shows significantly better results in breast cancer.
    CONCLUSIONS: KDM4A silences BMP9 expression by removing histone methyl groups from the BMP9 gene region, leading to further enhancement of glutamine metabolism, which contributes to malignant tumor progression. In addition, using JIB-04 in combination with exogenous BMP9 could inhibit the malignant progression of breast cancer cells and the growth of tumors more significantly.
    Keywords:  BMP9; Breast cancer; Glutamine metabolism; KDM4A
    DOI:  https://doi.org/10.1186/s12935-024-03504-0
  5. ACS Med Chem Lett. 2024 Sep 12. 15(9): 1430-1432
    Advancements in Targeted Therapeutics: Integrating Metabolic Modulation, Immune Engineering, and Biologic Formulation Technologies.
    Robert B Kargbo.
      The rapid advancement of targeted therapeutics has significantly improved treatment precision and efficacy in oncology and metabolic disorders. This article integrates key developments in four areas: highly selective PPAR modulators for metabolic and inflammatory diseases; CRISPR-engineered T-cell receptor therapies targeting the KRAS G12D mutation in cancer; strategies to enhance antitumor immunity through glutamine metabolism modulation in the tumor microenvironment; and a novel system for analyzing coformulated biologics. These innovations highlight the integration of metabolic modulation, immune system engineering, and advanced biologic formulation, paving the way for more effective and personalized therapeutic approaches.
    DOI:  https://doi.org/10.1021/acsmedchemlett.4c00404
  6. Cold Spring Harb Perspect Med. 2024 Sep 16. pii: a041553. [Epub ahead of print]
    Technologies for Decoding Cancer Metabolism with Spatial Resolution.
    Walter W Chen, Michael E Pacold, David M Sabatini, Naama Kanarek.
      It is increasingly appreciated that cancer cells adapt their metabolic pathways to support rapid growth and proliferation as well as survival, often even under the poor nutrient conditions that characterize some tumors. Cancer cells can also rewire their metabolism to circumvent chemotherapeutics that inhibit core metabolic pathways, such as nucleotide synthesis. A critical approach to the study of cancer metabolism is metabolite profiling (metabolomics), the set of technologies, usually based on mass spectrometry, that allow for the detection and quantification of metabolites in cancer cells and their environments. Metabolomics is a burgeoning field, driven by technological innovations in mass spectrometers, as well as novel approaches to isolate cells, subcellular compartments, and rare fluids, such as the interstitial fluid of tumors. Here, we discuss three emerging metabolomic technologies: spatial metabolomics, single-cell metabolomics, and organellar metabolomics. The use of these technologies along with more established profiling methods, like single-cell transcriptomics and proteomics, is likely to underlie new discoveries and questions in cancer research.
    DOI:  https://doi.org/10.1101/cshperspect.a041553
  7. Dis Model Mech. 2024 Sep 01. pii: dmm050814. [Epub ahead of print]17(9):
    Metabolic ripple effects - deciphering how lipid metabolism in cancer interfaces with the tumor microenvironment.
    Patrick B Jonker, Alexander Muir.
      Cancer cells require a constant supply of lipids. Lipids are a diverse class of hydrophobic molecules that are essential for cellular homeostasis, growth and survival, and energy production. How tumors acquire lipids is under intensive investigation, as these mechanisms could provide attractive therapeutic targets for cancer. Cellular lipid metabolism is tightly regulated and responsive to environmental stimuli. Thus, lipid metabolism in cancer is heavily influenced by the tumor microenvironment. In this Review, we outline the mechanisms by which the tumor microenvironment determines the metabolic pathways used by tumors to acquire lipids. We also discuss emerging literature that reveals that lipid availability in the tumor microenvironment influences many metabolic pathways in cancers, including those not traditionally associated with lipid biology. Thus, metabolic changes instigated by the tumor microenvironment have 'ripple' effects throughout the densely interconnected metabolic network of cancer cells. Given the interconnectedness of tumor metabolism, we also discuss new tools and approaches to identify the lipid metabolic requirements of cancer cells in the tumor microenvironment and characterize how these requirements influence other aspects of tumor metabolism.
    Keywords:  Acidosis; Diet; Hypoxia; Lipid metabolism; Nutrient deprivation; Tumor microenvironment
    DOI:  https://doi.org/10.1242/dmm.050814
  8. Adv Clin Exp Med. 2024 Sep 20.
    Novel strategies of glutathione depletion in photodynamic and chemodynamic therapy: A review.
    Daniel Wolny, Mateusz Stojko, Alicja Zajdel.
      Cancer remains a health problem worldwide; therefore, developing new therapies to increase the effectiveness of anticancer treatments is necessary. Two such methods are photodynamic therapy (PDT) and chemodynamic therapy (CDT). The intensive growth and increased metabolism of tumors lead to elevated levels of reactive oxygen species (ROS) within cancer cells. These cells develop several antioxidant mechanisms to protect them from this oxidative stress. Antioxidants also make tumors more resistant to chemotherapy and radiation. Glutathione (GSH) is an important and the most abundant endogenous cellular antioxidant. Photodynamic therapy and CDT are new methods that are based on the production of ROS,‑ therefore increasing oxidative stress in cancer cells. A significant problem with these therapies is the increased GSH levels, which is an adaptation of cancer cells to augmented metabolic processes. This paper presents various GSH depletion strategies that are used to improve PDT and CDT. While the main goal of GSH depletion in both PDT and CDT is to prevent its interaction with the ROS generated by these therapies, it should be remembered that the reduction of its level itself may initiate pathways leading to cancer cell death.
    Keywords:  chemodynamic therapy; glutathione depletion; photodynamic therapy
    DOI:  https://doi.org/10.17219/acem/191025
  9. Cancer Res. 2024 Sep 16. 84(18): 2947-2949
    Nutrient Levels and Nutrient Sources in Pancreatic Tumors.
    Sven Groessl, Wilhelm Palm.
      It has been known that poor tumor perfusion and dysregulated cancer cell metabolism give rise to tumor microenvironments with unphysiologic nutrient levels, but the precise alterations in metabolite abundance are not well defined. In a 2015 study in Cancer Research, Kamphorst and colleagues published a detailed comparison of the metabolome from human pancreatic tumors and benign tissues. Tumors were depleted in glucose and various nonessential amino acids but, surprisingly, enriched in essential amino acids. The authors attributed these nutrient imbalances to macropinocytosis of extracellular proteins, a RAS-driven amino acid acquisition pathway that was found to be increased in human tumors and supports pancreatic cancer cell growth during amino acid starvation. These findings substantially contributed to the understanding of altered nutrient levels in tumors and extracellular proteins as noncanonical nutrients. Intratumoral nutrient levels in different cancer contexts and signaling pathways that regulate nutrient acquisition by cancer cells remain a focus of current research. See related article by Kamphorst and colleagues, Cancer Res 2015;75:544-53.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-2447
  10. Bioact Mater. 2024 Dec;42 178-193
    An immunotherapeutic hydrogel booster inhibits tumor recurrence and promotes wound healing for postoperative management of melanoma.
    Yuanyuan Yang, Bo Zhang, Yangtao Xu, Wenxiang Zhu, Zinian Zhu, Xibo Zhang, Wenze Wu, Jierong Chen, Zhiqiang Yu.
      Low tumor immunogenicity, immunosuppressive tumor microenvironment, and bacterial infections have emerged as significant challenges in postsurgical immunotherapy and skin regeneration for preventing melanoma recurrence. Herein, an immunotherapeutic hydrogel booster (GelMA-CJCNPs) was developed to prevent postoperative tumor recurrence and promote wound healing by incorporating ternary carrier-free nanoparticles (CJCNPs) containing chlorine e6 (Ce6), a BRD4 inhibitor (JQ1), and a glutaminase inhibitor (C968) into methacrylic anhydride-modified gelatin (GelMA) dressings. GelMA-CJCNPs reduced glutathione production by inhibiting glutamine metabolism, thereby preventing the destruction of reactive oxygen species generated by photodynamic therapy, which could amplify oxidative stress to induce severe cell death and enhance immunogenic cell death. In addition, GelMA-CJCNPs reduced M2-type tumor-associated macrophage polarization by blocking glutamine metabolism to reverse the immunosuppressive tumor microenvironment, recruiting more tumor-infiltrating T lymphocytes. GelMA-CJCNPs also downregulated IFN-γ-induced expression of programmed cell death ligand 1 to mitigate acquired immune resistance. Benefiting from the amplified systemic antitumor immunity, GelMA-CJCNPs markedly inhibited the growth of both primary and distant tumors. Moreover, GelMA-CJCNPs demonstrated satisfactory photodynamic antibacterial effects against Staphylococcus aureus infections, thereby promoting postsurgical wound healing. Hence, this immunotherapeutic hydrogel booster, as a facile and effective postoperative adjuvant, possesses a promising potential for inhibiting tumor recurrence and accelerating skin regeneration.
    Keywords:  Glutamine metabolism; Hydrogel; Immunotherapy; Melanoma; Wound healing
    DOI:  https://doi.org/10.1016/j.bioactmat.2024.08.028
  11. Cold Spring Harb Perspect Med. 2024 Sep 16. pii: a041555. [Epub ahead of print]
    Cancer Metabolism: Aspirations for the Coming Decade.
    Ralph J DeBerardinis, Karen H Vousden, Navdeep S Chandel.
      Fueled by technological and conceptual advancements over the past two decades, research in cancer metabolism has begun to answer questions dating back to the time of Otto Warburg. But, as with most fields, new discoveries lead to new questions. This review outlines the emerging challenges that we predict will drive the next few decades of cancer metabolism research. These include developing a more realistic understanding of how metabolic activities are compartmentalized within cells, tissues, and organs; how metabolic preferences in tumors evolve during cancer progression from nascent, premalignant lesions to advanced, metastatic disease; and, most importantly, how we can best translate basic observations from preclinical models into novel therapies that benefit patients with cancer. With modern tools and an incredible amount of talent focusing on these problems, the upcoming decades should bring transformative discoveries.
    DOI:  https://doi.org/10.1101/cshperspect.a041555
  12. Trends Cancer. 2024 Sep 13. pii: S2405-8033(24)00172-9. [Epub ahead of print]
    Metabolism and epigenetics: drivers of tumor cell plasticity and treatment outcomes.
    Benjamin N Gantner, Flavio R Palma, Madhura R Pandkar, Marcelo J Sakiyama, Daniel Arango, Gina M DeNicola, Ana P Gomes, Marcelo G Bonini.
      Emerging evidence indicates that metabolism not only is a source of energy and biomaterials for cell division but also acts as a driver of cancer cell plasticity and treatment resistance. This is because metabolic changes lead to remodeling of chromatin and reprogramming of gene expression patterns, furthering tumor cell phenotypic transitions. Therefore, the crosstalk between metabolism and epigenetics seems to hold immense potential for the discovery of novel therapeutic targets for various aggressive tumors. Here, we highlight recent discoveries supporting the concept that the cooperation between metabolism and epigenetics enables cancer to overcome mounting treatment-induced pressures. We discuss how specific metabolites contribute to cancer cell resilience and provide perspective on how simultaneously targeting these key forces could produce synergistic therapeutic effects to improve treatment outcomes.
    Keywords:  cancer metabolism; epigenetics; histones; metabolites; novel therapeutics; post-translational modifications
    DOI:  https://doi.org/10.1016/j.trecan.2024.08.005
  13. Hereditas. 2024 Sep 19. 161(1): 35
    Glutamine metabolism-related genes predict the prognostic risk of acute myeloid leukemia and stratify patients by subtype analysis.
    Jie Zhou, Na Zhang, Yan Zuo, Feng Xu, Lihua Cheng, Yuanyuan Fu, Fudong Yang, Min Shu, Mi Zhou, Wenting Zou, Shengming Zhang.
       BACKGROUND: Acute myeloid leukemia (AML) is a genetically heterogeneous disease in which glutamine (Gln) contributes to AML progression. Therefore, this study aimed to identify potential prognostic biomarkers for AML based on Gln metabolism-related genes.
    METHODS: Gln-related genes that were differentially expressed between Cancer Genome Atlas-based AML and normal samples were analyzed using the limma package. Univariate, least absolute shrinkage, selection operators, and stepwise Cox regression analyses were used to identify prognostic signatures. Risk score-based prognostic and nomogram models were constructed to predict the prognostic risk of AML. Subsequently, consistent cluster analysis was performed to stratify patients into different subtypes, and subtype-related module genes were screened using weighted gene co-expression network analysis.
    RESULTS: Through a series of regression analyses, HGF, ANGPTL3, MB, F2, CALR, EIF4EBP1, EPHX1, and PDHA1 were identified as potential prognostic biomarkers of AML. Prognostic and nomogram models constructed based on these genes could significantly differentiate between high- and low-risk AML with high predictive accuracy. The eight-signature also stratified patients with AML into two subtypes, among which Cluster 2 was prone to a high risk of AML prognosis. These two clusters exhibited different immune profiles. Of the subtype-related module genes, the HOXA and HOXB family genes may be genetic features of AML subtypes.
    CONCLUSION: Eight Gln metabolism-related genes were identified as potential biomarkers of AML to predict prognostic risk. The molecular subtypes clustered by these genes enabled prognostic risk stratification.
    Keywords:  Acute myeloid leukemia; Glutamine; Immune infiltration; Molecular subtype; Prognostic model
    DOI:  https://doi.org/10.1186/s41065-024-00338-8
  14. Nat Cancer. 2024 Sep 19.
    Glutaminase inhibition in combination with azacytidine in myelodysplastic syndromes: a phase 1b/2 clinical trial and correlative analyses.
    Courtney D DiNardo, Divij Verma, Natalia Baran, Tushar D Bhagat, Anna Skwarska, Alessia Lodi, Kapil Saxena, Tianyu Cai, Xiaoping Su, Veronica A Guerra, Gowri Poigaialwar, Vinitha M Kuruvilla, Sergej Konoplev, Shanisha Gordon-Mitchell, Kith Pradhan, Srinivas Aluri, G Lavender Hackman, Sovira Chaudhry, Meghan Collins, Shannon R Sweeney, Jonathan Busquets, Atul Singh Rathore, Qing Deng, Michael R Green, Steven Grant, Susan Demo, Gaurav S Choudhary, Srabani Sahu, Beamon Agarwal, Mason Spodek, Victor Thiruthuvanathan, Britta Will, Ulrich Steidl, George D Tippett, Jan Burger, Gautam Borthakur, Elias Jabbour, Naveen Pemmaraju, Tapan Kadia, Steven Kornblau, Naval G Daver, Kiran Naqvi, Nicholas J Short, Guillermo Garcia-Manero, Stefano Tiziani, Amit Verma, Marina Konopleva.
      Malignancies are reliant on glutamine as an energy source and a facilitator of aberrant DNA methylation. We demonstrate preclinical synergy of telaglenastat (CB-839), a selective glutaminase inhibitor, combined with azacytidine (AZA), followed by a single-arm, open-label, phase 1b/2 study in persons with advanced myelodysplastic syndrome (MDS). The dual primary endpoints evaluated clinical activity, safety and tolerability; secondary endpoints evaluated pharmacokinetics, pharmacodynamics, overall survival, event-free survival and duration of response. The dose-escalation study included six participants and the dose-expansion study included 24 participants. Therapy was well tolerated and led to an objective response rate of 70% with (marrow) complete remission in 53% of participants and a median overall survival of 11.6 months, with evidence of myeloid differentiation in responders determined by single-cell RNA sequencing. Glutamine transporter solute carrier family 38 member 1 in MDS stem cells was associated with clinical responses and predictive of worse prognosis in a large MDS cohort. These data demonstrate the safety and efficacy of CB-839 and AZA as a combined metabolic and epigenetic approach in MDS. ClinicalTrials.gov identifier: NCT03047993 .
    DOI:  https://doi.org/10.1038/s43018-024-00811-3
  15. Phytother Res. 2024 Sep 17.
    Role of Glutathione in Parkinson's Disease Pathophysiology and Therapeutic Potential of Polyphenols.
    Chengu Niu, Miaoxian Dong, Yingcai Niu.
      Oxidative stress is recognized to have a central role in the initiation and progression of Parkinson's disease (PD). Within the brain, neurons are particularly sensitive to oxidation due in part to their weak intrinsic antioxidant defense. Theoretically, neurons mostly depend on neighboring astrocytes to provide antioxidant protection by supplying cysteine-containing products for glutathione (GSH) synthesis. Astrocytes and neurons possess several amino acid transport systems for GSH and its precursors. Indeed, GSH is the most abundant intrinsic antioxidant in the central nervous system. The GSH depletion and/or alterations in its metabolism in the brain contribute to the pathogenesis of PD. Noteworthy, polyphenols possess potent antioxidant activity and can augment the GSH redox system. Numerous in vitro and in vivo studies have indicated that polyphenols exhibit potent neuroprotective effects in PD. Epidemiological studies have found an association between the consumption of dietary polyphenols and a lower PD risk. In this review, we summarize current knowledge on the biosynthesis and metabolism of GSH in the brain, with an emphasis on their contribution and therapeutic potential in PD. In particular, we focus on polyphenols that can increase brain GSH levels against PD. Furthermore, some current challenges and future perspectives for polyphenol-based therapies are also discussed.
    Keywords:  Parkinson's disease; astrocytes; glutathione; neurons; polyphenols
    DOI:  https://doi.org/10.1002/ptr.8342
  16. Elife. 2024 Sep 17. pii: RP98834. [Epub ahead of print]13
    Bidirectional dysregulation of synaptic glutamate signaling after transient metabolic failure.
    Stefan Passlick, Ghanim Ullah, Christian Henneberger.
      Ischemia leads to a severe dysregulation of glutamate homeostasis and excitotoxic cell damage in the brain. Shorter episodes of energy depletion, for instance during peri-infarct depolarizations, can also acutely perturb glutamate signaling. It is less clear if such episodes of metabolic failure also have persistent effects on glutamate signaling and how the relevant mechanisms such as glutamate release and uptake are differentially affected. We modeled acute and transient metabolic failure by using a chemical ischemia protocol and analyzed its effect on glutamatergic synaptic transmission and extracellular glutamate signals by electrophysiology and multiphoton imaging, respectively, in the mouse hippocampus. Our experiments uncover a duration-dependent bidirectional dysregulation of glutamate signaling. Whereas short chemical ischemia induces a lasting potentiation of presynaptic glutamate release and synaptic transmission, longer episodes result in a persistent postsynaptic failure of synaptic transmission. We also observed unexpected differences in the vulnerability of the investigated cellular mechanisms. Axonal action potential firing and glutamate uptake were surprisingly resilient compared to postsynaptic cells, which overall were most vulnerable to acute and transient metabolic stress. We conclude that short perturbations of energy supply lead to a lasting potentiation of synaptic glutamate release, which may increase glutamate excitotoxicity well beyond the metabolic incident.
    Keywords:  glutamate release; glutamate uptake; ischemia; metabolic failure; mouse; neuroscience; stroke; synaptic transmission
    DOI:  https://doi.org/10.7554/eLife.98834
  17. Int J Cancer. 2024 Sep 18.
    Metabolic regulation of the tumour and its microenvironment: The role of Epstein-Barr virus.
    Shen-Han Lee, Alan Soo-Beng Khoo, John R Griffiths, Norhafiza Mat Lazim.
      The Epstein-Barr virus (EBV), the first identified human tumour virus, infects over 95% of the individuals globally and has the potential to induce different types of cancers. It is increasingly recognised that EBV infection not only alters cellular metabolism, contributing to neoplastic transformation, but also utilises several non-cell autonomous mechanisms to shape the metabolic milieu in the tumour microenvironment (TME) and its constituent stromal and immune cells. In this review, we explore how EBV modulates metabolism to shape the interactions between cancer cells, stromal cells, and immune cells within a hypoxic and acidic TME. We highlight how metabolites resulting from EBV infection act as paracrine factors to regulate the TME, and how targeting them can disrupt barriers to immunotherapy.
    Keywords:  EBV‐associated malignancies; Epstein–Barr virus; nasopharyngeal cancer; tumour metabolism; tumour microenvironment
    DOI:  https://doi.org/10.1002/ijc.35192
  18. Mol Cancer. 2024 Sep 18. 23(1): 202
    Spatiotemporal metabolomic approaches to the cancer-immunity panorama: a methodological perspective.
    Yang Xiao, Yongsheng Li, Huakan Zhao.
      Metabolic reprogramming drives the development of an immunosuppressive tumor microenvironment (TME) through various pathways, contributing to cancer progression and reducing the effectiveness of anticancer immunotherapy. However, our understanding of the metabolic landscape within the tumor-immune context has been limited by conventional metabolic measurements, which have not provided comprehensive insights into the spatiotemporal heterogeneity of metabolism within TME. The emergence of single-cell, spatial, and in vivo metabolomic technologies has now enabled detailed and unbiased analysis, revealing unprecedented spatiotemporal heterogeneity that is particularly valuable in the field of cancer immunology. This review summarizes the methodologies of metabolomics and metabolic regulomics that can be applied to the study of cancer-immunity across single-cell, spatial, and in vivo dimensions, and systematically assesses their benefits and limitations.
    Keywords:  Cancer-immunity; Immunometabolism; Metabolic regulomics; Metabolomics; Single cell; Spatiotemporal omics
    DOI:  https://doi.org/10.1186/s12943-024-02113-9
  19. Cancer Lett. 2024 Sep 12. pii: S0304-3835(24)00653-0. [Epub ahead of print]604 217258
    Macroautophagy/autophagy promotes resistance to KRASG12D-targeted therapy through glutathione synthesis.
    Leng Han, Lingjun Meng, Jiao Liu, Yangchun Xie, Rui Kang, Daniel J Klionsky, Daolin Tang, Yuanyuan Jia, Enyong Dai.
      KRASG12D mutation-driven pancreatic ductal adenocarcinoma (PDAC) represents a major challenge in medicine due to late diagnosis and treatment resistance. Here, we report that macroautophagy (hereafter autophagy), a cellular degradation and recycling process, contributes to acquired resistance against novel KRASG12D-targeted therapy. The KRASG12D protein inhibitor MRTX1133 induces autophagy in KRASG12D-mutated PDAC cells by blocking MTOR activity, and increased autophagic flux prevents apoptosis. Mechanistically, autophagy facilitates the generation of glutamic acid, cysteine, and glycine for glutathione synthesis. Increased glutathione levels reduce reactive oxygen species production, which impedes CYCS translocation from mitochondria to the cytosol, ultimately preventing the formation of the APAF1 apoptosome. Consequently, genetic interventions (utilizing ATG5 or BECN1 knockout) or pharmacological inhibition of autophagy (with chloroquine, bafilomycin A1, or spautin-1) enhance the anticancer activity of MRTX1133 in vitro and in various animal models (subcutaneous, patient-derived xenograft, and orthotopic). Moreover, the release of histones by apoptotic cells triggers an adaptive immune response when combining an autophagy inhibitor with MRTX1133 in immunocompetent mice. These findings establish a new strategy to overcome KRASG12D-targeted therapy resistance by inhibiting autophagy-dependent glutathione synthesis.
    Keywords:  Autophagy; Drug resistance; Glutathione; KRAS mutation; Pancreatic cancer
    DOI:  https://doi.org/10.1016/j.canlet.2024.217258
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