دورية أكاديمية
In vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma.
| العنوان: | In vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma. |
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| المؤلفون: | Kaushik AK; Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA., Tarangelo A; Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA., Boroughs LK; Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA., Ragavan M; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Zhang Y; Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA., Wu CY; Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA., Li X; Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA., Ahumada K; Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA., Chiang JC; Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA., Tcheuyap VT; Kidney Cancer Program, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA., Saatchi F; Kidney Cancer Program, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA., Do QN; Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA., Yong C; Department of Surgery, University of Cambridge, Cambridge, UK., Rosales T; Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA., Stevens C; Kidney Cancer Program, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA., Rao AD; Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria 3010, Australia., Faubert B; Department of Medicine, The University of Chicago, Chicago, IL, USA., Pachnis P; Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA., Zacharias LG; Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA., Vu H; Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA., Cai F; Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA., Mathews TP; Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA., Genovese G; Department of Genitourinary Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA., Slusher BS; Department of Neurology and Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD, USA., Kapur P; Kidney Cancer Program, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA., Sun X; Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Kidney Cancer Program, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX USA., Merritt M; Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, USA., Brugarolas J; Kidney Cancer Program, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA., DeBerardinis RJ; Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Kidney Cancer Program, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Howard Hughes Medical Institute, Chevy Chase, MD, USA. |
| المصدر: | Science advances [Sci Adv] 2022 Dec 16; Vol. 8 (50), pp. eabp8293. Date of Electronic Publication: 2022 Dec 16. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101653440 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2375-2548 (Electronic) Linking ISSN: 23752548 NLM ISO Abbreviation: Sci Adv Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, DC : American Association for the Advancement of Science, [2015]- |
| مواضيع طبية MeSH: | Carcinoma, Renal Cell*/drug therapy , Carcinoma, Renal Cell*/metabolism , Kidney Neoplasms*/drug therapy , Kidney Neoplasms*/pathology, Humans ; Mice ; Animals ; Glutaminase/therapeutic use ; Glutamine/metabolism ; Isocitrate Dehydrogenase |
| مستخلص: | Targeting metabolic vulnerabilities has been proposed as a therapeutic strategy in renal cell carcinoma (RCC). Here, we analyzed the metabolism of patient-derived xenografts (tumorgrafts) from diverse subtypes of RCC. Tumorgrafts from VHL -mutant clear cell RCC (ccRCC) retained metabolic features of human ccRCC and engaged in oxidative and reductive glutamine metabolism. Genetic silencing of isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 impaired reductive labeling of tricarboxylic acid (TCA) cycle intermediates in vivo and suppressed growth of tumors generated from tumorgraft-derived cells. Glutaminase inhibition reduced the contribution of glutamine to the TCA cycle and resulted in modest suppression of tumorgraft growth. Infusions with [amide- 15 N]glutamine revealed persistent amidotransferase activity during glutaminase inhibition, and blocking these activities with the amidotransferase inhibitor JHU-083 also reduced tumor growth in both immunocompromised and immunocompetent mice. We conclude that ccRCC tumorgrafts catabolize glutamine via multiple pathways, perhaps explaining why it has been challenging to achieve therapeutic responses in patients by inhibiting glutaminase. |
| التعليقات: | Comment in: Nat Rev Nephrol. 2023 Mar;19(3):151. doi: 10.1038/s41581-023-00684-2. (PMID: 36694057) |
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| معلومات مُعتمدة: | P41 GM122698 United States GM NIGMS NIH HHS; S10 OD028753 United States OD NIH HHS; K25 HD104004 United States HD NICHD NIH HHS; R35 CA220449 United States CA NCI NIH HHS; KL2 TR003981 United States TR NCATS NIH HHS; R01 DK132254 United States DK NIDDK NIH HHS; P50 CA196516 United States CA NCI NIH HHS; R00 CA237724 United States CA NCI NIH HHS |
| المشرفين على المادة: | EC 3.5.1.2 (Glutaminase) 0RH81L854J (Glutamine) EC 1.1.1.41 (Isocitrate Dehydrogenase) |
| تواريخ الأحداث: | Date Created: 20221216 Date Completed: 20221220 Latest Revision: 20240626 |
| رمز التحديث: | 20240626 |
| مُعرف محوري في PubMed: | PMC9757752 |
| DOI: | 10.1126/sciadv.abp8293 |
| PMID: | 36525494 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2375-2548 |
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| DOI: | 10.1126/sciadv.abp8293 |