bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2024–09–01
seven papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. GCN2 drives diurnal patterns in the hepatic integrated stress response and maintains circadian rhythms in whole body metabolism during amino acid insufficiency.
  2. The Effects of Hypoxia on the Immune-Metabolic Interplay in Liver Cancer.
  3. From sweat to hope: The role of exercise-induced extracellular vesicles in cancer prevention and treatment.
  4. Secreted GDF15 maintains transcriptional responses during DNA damage-mediated senescence in human β-cells.
  5. The role of metabolic reprogramming in immune escape of triple-negative breast cancer.
  6. The stress-responsive gene ATF3 drives fibroblast activation and collagen production through transcriptionally activating TGF-β receptor Ⅱ in skin wound healing.
  7. The glycolytic metabolite methylglyoxal covalently inactivates the NLRP3 inflammasome.
  1. Am J Physiol Endocrinol Metab. 2024 Aug 28.
    GCN2 drives diurnal patterns in the hepatic integrated stress response and maintains circadian rhythms in whole body metabolism during amino acid insufficiency.
    Jordan L Levy, Emily T Mirek, Esther M Rodriguez, Maria J Tolentino, Brian Zalma, Troy A Roepke, Ronald C Wek, Ruifeng Cao, Tracy G Anthony.
      Disruptions in circadian rhythms are associated with increased risk of developing metabolic diseases. General control nonderepressible 2 (GCN2), a primary sensor of amino acid insufficiency and activator of the integrated stress response (ISR), has emerged as a conserved regulator of the circadian clock in multiple organisms. The objective of this study was to examine diurnal patterns in hepatic ISR activation in the liver and whole-body rhythms in metabolism. We hypothesized that GCN2 activation cues hepatic ISR signaling over a natural 24 h feeding fasting cycle. To address our objective, wild type (WT) and whole body Gcn2 knockout (GCN2 KO) mice were housed in metabolic cages and provided free access to either a Control or leucine-devoid diet (LeuD) for 8-days in total darkness. On the last day, blood and livers were collected at circadian time (CT) 3 and CT15. In livers of WT mice, GCN2 phosphorylation followed a diurnal pattern that was guided by intracellular branched chain amino acid concentrations (r2=0.93). Feeding LeuD to WT mice increased hepatic ISR activation at CT15 only. Diurnal oscillation in hepatic ISR signaling, the hepatic transcriptome including lipid metabolic genes, and triglyceride concentrations were substantially reduced or absent in GCN2 KO mice. Further, mice lacking GCN2 were unable to maintain circadian rhythms in whole body energy expenditure, respiratory exchange ratio and physical activity when fed LeuD. In conclusion, GCN2 activation functions to maintain diurnal ISR activation in the liver and has a vital role in the mechanisms by which nutrient stress affects whole-body metabolism.
    Keywords:  RNA sequencing; dietary protein quality; eukaryotic initiation factor 2 (eIF2); peripheral circadian clock
    DOI:  https://doi.org/10.1152/ajpendo.00129.2024
  2. Biomolecules. 2024 Aug 17. pii: 1024. [Epub ahead of print]14(8):
    The Effects of Hypoxia on the Immune-Metabolic Interplay in Liver Cancer.
    Yubei He, Han Xu, Yu Liu, Stefan Kempa, Carolina Vechiatto, Robin Schmidt, Emine Yaren Yilmaz, Luisa Heidemann, Jörg Schnorr, Susanne Metzkow, Eyk Schellenberger, Akvile Häckel, Andreas Patzak, Dominik N Müller, Lynn Jeanette Savic.
      M2-like macrophages promote tumor growth and cancer immune evasion. This study used an in vitro model to investigate how hypoxia and tumor metabolism affect macrophage polarization. Liver cancer cells (HepG2 and VX2) and macrophages (THP1) were cultured under hypoxic (0.1% O2) and normoxic (21% O2) conditions with varying glucose levels (2 g/L or 4.5 g/L). Viability assays and extracellular pH (pHe) measurements were conducted over 96 hours. Macrophages were exposed to the tumor-conditioned medium (TCM) from the cancer cells, and polarization was assessed using arginase and nitrite assays. GC-MS-based metabolic profiling quantified TCM meta-bolites and correlated them with M2 polarization. The results showed that pHe in TCMs decreased more under hypoxia than normoxia (p < 0.0001), independent of glucose levels. The arginase assay showed hypoxia significantly induced the M2 polarization of macrophages (control group: p = 0.0120,0.1%VX2-TCM group: p = 0.0149, 0.1%HepG2-TCM group: p < 0.0001, 0.1%VX2-TCMHG group: p = 0.0001, and 0.1%HepG2-TCMHG group: p < 0.0001). TCMs also induced M2 polarization under normoxic conditions, but the strongest M2 polarization occurred when both tumor cells and macrophages were incubated under hypoxia with high glucose levels. Metabolomics revealed that several metabolites, particularly lactate, were correlated with hypoxia and M2 polarization. Under normoxia, elevated 2-amino-butanoic acid (2A-BA) strongly correlated with M2 polarization. These findings suggest that targeting tumor hypoxia could mitigate immune evasion in liver tumors. Lactate drives acidity in hypoxic tumors, while 2A-BA could be a therapeutic target for overcoming immunosuppression in normoxic conditions.
    Keywords:  2-amino-butanoic acid (2A-BA); GC-MS-based metabolic profiling; M2-like polarization; hepatocellular carcinoma (HCC); hypoxia
    DOI:  https://doi.org/10.3390/biom14081024
  3. J Extracell Vesicles. 2024 Aug;13(8): e12500
    From sweat to hope: The role of exercise-induced extracellular vesicles in cancer prevention and treatment.
    Alicia Llorente, Agnese Brokāne, Agata Mlynska, Marju Puurand, Krizia Sagini, Signe Folkmane, Marit Hjorth, Beatriz Martin-Gracia, Silvana Romero, Diana Skorinkina, Mārtiņš Čampa, Rūdolfs Cešeiko, Nadezhda Romanchikova, Aija Kļaviņa, Tuuli Käämbre, Aija Linē.
      The benefits of regular physical exercise on cancer prevention, as well as reducing fatigue, treatment side effects and recurrence, and improving quality of life and overall survival of cancer patients, are increasingly recognised. Initial studies showed that the concentration of extracellular vesicles (EVs) increases during physical activity and that EVs carry biologically active cargo. These EVs are released by blood cells, skeletal muscle and other organs involved in exercise, thus suggesting that EVs may mediate tissue crosstalk during exercise. This possibility triggered a great interest in the study of the roles of EVs in systemic adaptation to exercise and in their potential applications in the prevention and treatment of various diseases, including cancer. This review presents studies exploring the concentration and molecular cargo of EVs released during exercise. Furthermore, we discuss putative stimuli that may trigger EV release from various cell types, the biological functions and the impact of exercise-induced EVs on cancer development and progression. Understanding the interplay between exercise, EVs, and cancer biology may offer insights into novel therapeutic strategies and preventive measures for cancer.
    Keywords:  EV RNA cargo; EV protein cargo; cancer; exercise‐induced extracellular vesicles; muscle‐derived EVs; physical exercise
    DOI:  https://doi.org/10.1002/jev2.12500
  4. Am J Physiol Endocrinol Metab. 2024 Aug 28.
    Secreted GDF15 maintains transcriptional responses during DNA damage-mediated senescence in human β-cells.
    Nayara Rampazzo Morelli, Camille Préfontaine, Jasmine Pipella, Peter J Thompson.
      Type 1 Diabetes (T1D) is a chronic metabolic disease resulting from autoimmune destruction of pancreatic beta cells. Beta cells activate a variety of stress responses during the development of T1D, including senescence, which involves cell cycle arrest, prosurvival signaling and a proinflammatory secretome termed the senescence-associated secretory phenotype (SASP). We previously identified growth and differentiation factor 15 (GDF15) as a major SASP factor in human islets and human EndoC-βH5 beta cells in a model of DNA damage-mediated senescence that recapitulates features of senescent beta cells in T1D. Soluble GDF15 has been shown to exert protective effects on human and mouse beta cells during various forms of stress relevant to T1D, therefore we hypothesized that secreted GDF15 may play a prosurvival role during DNA damage-mediated senescence in human beta cells. We found that elevated GDF15 secretion was associated with endogenous senescent beta cells in an islet preparation from a T1D donor, supporting the validity of our DNA damage model. Using antibody-based neutralization, we found that secreted endogenous GDF15 was not required for senescent human islet or EndoC cell viability. Rather, neutralization of GDF15 led to reduced expression of specific senescence-associated genes, including GDF15 itself and the prosurvival gene BCL2L1. Taken together, these data suggest that SASP factor GDF15 is not required to sustain senescent human islet viability, but it is required to maintain senescence-associated transcriptional responses.
    Keywords:  Cellular senescence; DNA damage response; GDF15; Pancreatic beta cells; Senescence associated secretory phenotype
    DOI:  https://doi.org/10.1152/ajpendo.00257.2024
  5. Front Immunol. 2024 ;15 1424237
    The role of metabolic reprogramming in immune escape of triple-negative breast cancer.
    Ruochen Bao, Hongtao Qu, Baifeng Li, Kai Cheng, Yandong Miao, Jiangtao Wang.
      Triple-negative breast cancer (TNBC) has become a thorny problem in the treatment of breast cancer because of its high invasiveness, metastasis and recurrence. Although immunotherapy has made important progress in TNBC, immune escape caused by many factors, especially metabolic reprogramming, is still the bottleneck of TNBC immunotherapy. Regrettably, the mechanisms responsible for immune escape remain poorly understood. Exploring the mechanism of TNBC immune escape at the metabolic level provides a target and direction for follow-up targeting or immunotherapy. In this review, we focus on the mechanism that TNBC affects immune cells and interstitial cells through hypoxia, glucose metabolism, lipid metabolism and amino acid metabolism, and changes tumor metabolism and tumor microenvironment. This will help to find new targets and strategies for TNBC immunotherapy.
    Keywords:  amino acid metabolism; glucose metabolism; hypoxia; immune escape; lipid metabolism; triple-negative breast cancer
    DOI:  https://doi.org/10.3389/fimmu.2024.1424237
  6. Arch Biochem Biophys. 2024 Aug 23. pii: S0003-9861(24)00256-X. [Epub ahead of print]760 110134
    The stress-responsive gene ATF3 drives fibroblast activation and collagen production through transcriptionally activating TGF-β receptor Ⅱ in skin wound healing.
    Peng Luo, Fulong Wang, Jialun Li, Gaoyu Liu, Qin Xiong, Benhuang Yan, Xiaohui Cao, Bao Liu, Yang Wang, Gang Wu, Chunmeng Shi.
      Skin wound is an emerging health challenge on account of the high-frequency trauma, surgery and chronic refractory ulcer. Further study on the disease biology will help to develop new effective approaches for wound healing. Here, we identified a wound-stress responsive gene, activating transcription factor 3 (ATF3), and then investigated its biological action and mechanism in wound healing. In the full-thickness skin wound model, ATF3 was found to promote fibroblast activation and collagen production, resulted in accelerated wound healing. Mechanically, ATF3 transcriptionally activated TGF-β receptor Ⅱ via directly binding to its specific promoter motif, followed by the enhanced TGF-β/Smad pathway in fibroblasts. Moreover, the increased ATF3 upon skin injury was partly resulted from hypoxia stimulation with Hif-1α dependent manner. Altogether, this work gives novel insights into the biology and mechanism of stress-responsive gene ATF3 in wound healing, and provides a potential therapeutic target for treatment.
    Keywords:  Activating transcription factor 3; Collagen; Fibroblast; Skin wound healing; TGF-β receptor Ⅱ
    DOI:  https://doi.org/10.1016/j.abb.2024.110134
  7. Cell Rep. 2024 Aug 27. pii: S2211-1247(24)01039-8. [Epub ahead of print]43(9): 114688
    The glycolytic metabolite methylglyoxal covalently inactivates the NLRP3 inflammasome.
    Caroline Stanton, Chavin Buasakdi, Jie Sun, Ian Levitan, Prerona Bora, Sergei Kutseikin, R Luke Wiseman, Michael J Bollong.
      The NLRP3 inflammasome promotes inflammation in disease, yet the full repertoire of mechanisms regulating its activity is not well delineated. Among established regulatory mechanisms, covalent modification of NLRP3 has emerged as a common route for the pharmacological inactivation of this protein. Here, we show that inhibition of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) results in the accumulation of methylglyoxal, a reactive metabolite whose increased levels decrease NLRP3 assembly and inflammatory signaling in cells. We find that methylglyoxal inactivates NLRP3 via a non-enzymatic, covalent-crosslinking-based mechanism, promoting inter- and intraprotein MICA (methyl imidazole crosslink between cysteine and arginine) posttranslational linkages within NLRP3. This work establishes NLRP3 as capable of sensing a host of electrophilic chemicals, both exogenous small molecules and endogenous reactive metabolites, and suggests a mechanism by which glycolytic flux can moderate the activation status of a central inflammatory signaling pathway.
    Keywords:  CP: Immunology; CP: Metabolism; MICA modification; NLRP3; PGK1; covalent; glycolysis; inflammasome; inflammation; methylglyoxal
    DOI:  https://doi.org/10.1016/j.celrep.2024.114688
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