دورية أكاديمية
أعرض في EDS

OGDH and Bcl-xL loss causes synthetic lethality in glioblastoma.

التفاصيل البيبلوغرافية
العنوان: OGDH and Bcl-xL loss causes synthetic lethality in glioblastoma.
المؤلفون: Nguyen TT; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA., Torrini C; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA., Shang E; Department of Biological Sciences, Bronx Community College, City University of New York, New York, USA., Shu C; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA., Mun JY; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA., Gao Q; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA., Humala N; Department of Neurological Surgery, and., Akman HO; Department of Neurology, Columbia University Medical Center, New York, New York, USA., Zhang G; Proteomics and Metabolomics Core Facility, Weill Cornell Medicine, New York, New York, USA., Westhoff MA; Department of Pediatrics and Adolescent Medicine, and., Karpel-Massler G; Department of Neurosurgery, Ulm University Medical Center, Ulm, Germany., Bruce JN; Department of Neurological Surgery, and., Canoll P; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA., Siegelin MD; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA.
المصدر: JCI insight [JCI Insight] 2024 Mar 14; Vol. 9 (8). Date of Electronic Publication: 2024 Mar 14.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 101676073 Publication Model: Electronic Cited Medium: Internet ISSN: 2379-3708 (Electronic) Linking ISSN: 23793708 NLM ISO Abbreviation: JCI Insight Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Ann Arbor, Michigan : American Society for Clinical Investigation, [2016]-
مواضيع طبية MeSH: Aniline Compounds*/pharmacology , bcl-X Protein*/metabolism , bcl-X Protein*/genetics , Caprylates* , Glioblastoma*/pathology , Glioblastoma*/genetics , Glioblastoma*/metabolism , Glioblastoma*/drug therapy , Ketoglutarate Dehydrogenase Complex*/metabolism , Ketoglutarate Dehydrogenase Complex*/genetics , Ketoglutarate Dehydrogenase Complex*/antagonists & inhibitors , Sulfides* , Sulfonamides*/pharmacology , Synthetic Lethal Mutations* , Xenograft Model Antitumor Assays*, Animals ; Humans ; Mice ; Activating Transcription Factor 4/metabolism ; Activating Transcription Factor 4/genetics ; Brain Neoplasms/pathology ; Brain Neoplasms/metabolism ; Brain Neoplasms/genetics ; Brain Neoplasms/drug therapy ; Cell Line, Tumor ; Citric Acid Cycle/drug effects ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Proto-Oncogene Proteins c-bcl-2/genetics
مستخلص: Glioblastoma (GBM) remains an incurable disease, requiring more effective therapies. Through interrogation of publicly available CRISPR and RNAi library screens, we identified the α-ketoglutarate dehydrogenase (OGDH) gene, which encodes an enzyme that is part of the tricarboxylic acid (TCA) cycle, as essential for GBM growth. Moreover, by combining transcriptome and metabolite screening analyses, we discovered that loss of function of OGDH by the clinically validated drug compound CPI-613 was synthetically lethal with Bcl-xL inhibition (genetically and through the clinically validated BH3 mimetic, ABT263) in patient-derived xenografts as well neurosphere GBM cultures. CPI-613-mediated energy deprivation drove an integrated stress response with an upregulation of the BH3-only domain protein, Noxa, in an ATF4-dependent manner, as demonstrated by genetic loss-of-function experiments. Consistently, silencing of Noxa attenuated cell death induced by CPI-613 in model systems of GBM. In patient-derived xenograft models of GBM in mice, the combination treatment of ABT263 and CPI-613 suppressed tumor growth and extended animal survival more potently than each compound on its own. Therefore, combined inhibition of Bcl-xL along with disruption of the TCA cycle might be a treatment strategy for GBM.
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معلومات مُعتمدة: R01 NS095848 United States NS NINDS NIH HHS; S10 RR027050 United States RR NCRR NIH HHS; P30 CA013696 United States CA NCI NIH HHS; R01 NS113793 United States NS NINDS NIH HHS; R01 NS102366 United States NS NINDS NIH HHS
فهرسة مساهمة: Keywords: Apoptosis pathways; Oncology
المشرفين على المادة: 145891-90-3 (Activating Transcription Factor 4)
0 (Aniline Compounds)
0 (bcl-X Protein)
0 (BCL2L1 protein, human)
0 (Caprylates)
E76113IR49 (devimistat)
EC 1.2.4.2 (Ketoglutarate Dehydrogenase Complex)
XKJ5VVK2WD (navitoclax)
0 (PMAIP1 protein, human)
0 (Proto-Oncogene Proteins c-bcl-2)
0 (Sulfides)
0 (Sulfonamides)
0 (ELK1 protein, human)
تواريخ الأحداث: Date Created: 20240314 Date Completed: 20240423 Latest Revision: 20240603
رمز التحديث: 20240603
مُعرف محوري في PubMed: PMC11141877
DOI: 10.1172/jci.insight.172565
PMID: 38483541
قاعدة البيانات: MEDLINE
الوصف
تدمد:2379-3708
DOI:10.1172/jci.insight.172565