دورية أكاديمية
أعرض في EDS

Downregulation of Glutamine Synthetase, not glutaminolysis, is responsible for glutamine addiction in Notch1-driven acute lymphoblastic leukemia.

التفاصيل البيبلوغرافية
العنوان: Downregulation of Glutamine Synthetase, not glutaminolysis, is responsible for glutamine addiction in Notch1-driven acute lymphoblastic leukemia.
المؤلفون: Nguyen TL; Institut Européen de Chimie et Biologie, INSERM U1218, Université de Bordeaux, Pessac, France., Nokin MJ; Institut Européen de Chimie et Biologie, INSERM U1218, Université de Bordeaux, Pessac, France., Terés S; Institut Européen de Chimie et Biologie, INSERM U1218, Université de Bordeaux, Pessac, France., Tomé M; Centro Andaluz de Biología Molecular y Medicina Regenerativa - CABIMER, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Universidad Pablo de Olavide, Seville, Spain.; Angiogenesis and Cancer Microenvironment Laboratory INSERM U1029, Université de Bordeaux, Pessac, France., Bodineau C; Institut Européen de Chimie et Biologie, INSERM U1218, Université de Bordeaux, Pessac, France.; Centro Andaluz de Biología Molecular y Medicina Regenerativa - CABIMER, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Universidad Pablo de Olavide, Seville, Spain., Galmar O; Institut Européen de Chimie et Biologie, INSERM U1218, Université de Bordeaux, Pessac, France., Pasquet JM; INSERM, BMGIC, U1035, University of Bordeaux, France., Rousseau B; Service Commun des Animaleries, University of Bordeaux, France., van Liempd S; Exosomes Laboratory and Platform of Metabolomics, CIC bioGUNE, CIBERehd, Derio, Spain., Falcon-Perez JM; Exosomes Laboratory and Platform of Metabolomics, CIC bioGUNE, CIBERehd, Derio, Spain.; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain., Richard E; Institut Bergonié, INSERM U1218, University of Bordeaux, France., Muzotte E; INSERM, BMGIC, U1035, University of Bordeaux, France., Rezvani HR; INSERM, BMGIC, U1035, University of Bordeaux, France., Priault M; Institut de Biochimie et Génétique Cellulaires, CNRS UMR 5095, Université de Bordeaux, France., Bouchecareilh M; Bordeaux Research in Translational Oncology, INSERM U1053, Université de Bordeaux, France., Redonnet-Vernhet I; Maladies Héréditaires du Métabolisme, Laboratoire de Biochimie, Hôpital Pellegrin, CHU Bordeaux, France., Calvo J; UMR967, Inserm, CEA, Université Paris 7, Université Paris 11, Fontenay-aux-Roses, France., Uzan B; UMR967, Inserm, CEA, Université Paris 7, Université Paris 11, Fontenay-aux-Roses, France., Pflumio F; UMR967, Inserm, CEA, Université Paris 7, Université Paris 11, Fontenay-aux-Roses, France., Fuentes P; Centro de Biología Molecular 'Severo Ochoa', Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Spain., Toribio ML; Centro de Biología Molecular 'Severo Ochoa', Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Spain., Khatib AM; Angiogenesis and Cancer Microenvironment Laboratory INSERM U1029, Université de Bordeaux, Pessac, France., Soubeyran P; Institut Bergonié, INSERM U1218, University of Bordeaux, France., Murdoch PDS; Centro Andaluz de Biología Molecular y Medicina Regenerativa - CABIMER, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Universidad Pablo de Olavide, Seville, Spain.; Departamento de Bioquímica Vegetal y Biología Molecular, Universidad de Sevilla, Spain., Durán RV; Institut Européen de Chimie et Biologie, INSERM U1218, Université de Bordeaux, Pessac, France.; Centro Andaluz de Biología Molecular y Medicina Regenerativa - CABIMER, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Universidad Pablo de Olavide, Seville, Spain.
المصدر: Molecular oncology [Mol Oncol] 2021 May; Vol. 15 (5), pp. 1412-1431. Date of Electronic Publication: 2021 Feb 13.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: John Wiley & Sons, Inc Country of Publication: United States NLM ID: 101308230 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-0261 (Electronic) Linking ISSN: 15747891 NLM ISO Abbreviation: Mol Oncol Subsets: MEDLINE
أسماء مطبوعة: Publication: 2017- : Hoboken, New Jersey : John Wiley & Sons, Inc.
Original Publication: Amsterdam : Elsevier
مواضيع طبية MeSH: Glutamate-Ammonia Ligase/*genetics , Glutamine/*metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/*genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/*metabolism, Animals ; Cell Line, Tumor ; Down-Regulation/genetics ; Gene Expression Regulation, Enzymologic ; Gene Expression Regulation, Leukemic ; Glutamate-Ammonia Ligase/metabolism ; Humans ; Male ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Mice ; Mice, Inbred NOD ; Mice, Transgenic ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology ; Receptor, Notch1/genetics ; Receptor, Notch1/metabolism ; Signal Transduction/genetics
مستخلص: The cellular receptor Notch1 is a central regulator of T-cell development, and as a consequence, Notch1 pathway appears upregulated in > 65% of the cases of T-cell acute lymphoblastic leukemia (T-ALL). However, strategies targeting Notch1 signaling render only modest results in the clinic due to treatment resistance and severe side effects. While many investigations reported the different aspects of tumor cell growth and leukemia progression controlled by Notch1, less is known regarding the modifications of cellular metabolism induced by Notch1 upregulation in T-ALL. Previously, glutaminolysis inhibition has been proposed to synergize with anti-Notch therapies in T-ALL models. In this work, we report that Notch1 upregulation in T-ALL induced a change in the metabolism of the important amino acid glutamine, preventing glutamine synthesis through the downregulation of glutamine synthetase (GS). Downregulation of GS was responsible for glutamine addiction in Notch1-driven T-ALL both in vitro and in vivo. Our results also confirmed an increase in glutaminolysis mediated by Notch1. Increased glutaminolysis resulted in the activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway, a central controller of cell growth. However, glutaminolysis did not play any role in Notch1-induced glutamine addiction. Finally, the combined treatment targeting mTORC1 and limiting glutamine availability had a synergistic effect to induce apoptosis and to prevent Notch1-driven leukemia progression. Our results placed glutamine limitation and mTORC1 inhibition as a potential therapy against Notch1-driven leukemia.
(© 2020 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
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فهرسة مساهمة: Keywords: Notch1; T-cell acute lymphoblastic leukemia; glutamine; glutamine synthetase; mTORC1; metabolic addiction
المشرفين على المادة: 0 (Receptor, Notch1)
0RH81L854J (Glutamine)
EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
EC 6.3.1.2 (Glutamate-Ammonia Ligase)
تواريخ الأحداث: Date Created: 20201214 Date Completed: 20220331 Latest Revision: 20220331
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC8096784
DOI: 10.1002/1878-0261.12877
PMID: 33314742
قاعدة البيانات: MEDLINE
الوصف
تدمد:1878-0261
DOI:10.1002/1878-0261.12877