دورية أكاديمية
Medium-Chain Acyl-CoA Dehydrogenase Protects Mitochondria from Lipid Peroxidation in Glioblastoma.
العنوان: | Medium-Chain Acyl-CoA Dehydrogenase Protects Mitochondria from Lipid Peroxidation in Glioblastoma. |
---|---|
المؤلفون: | Puca F; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. GDraetta@mdanderson.org AViale@mdanderson.org FPuca@mdanderson.org CLyssiot@med.umich.edu., Yu F; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas., Bartolacci C; Department of Internal Medicine Division of Hematology & Oncology, University of Cincinnati, Cincinnati, Ohio., Pettazzoni P; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas., Carugo A; The Translational Research to Advance Therapeutics and Innovation in Oncology Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas., Huang-Hobbs E; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas., Liu J; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas., Zanca C; The Translational Research to Advance Therapeutics and Innovation in Oncology Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas., Carbone F; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas., Del Poggetto E; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas., Gumin J; Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas., Dasgupta P; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas., Seth S; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.; The Translational Research to Advance Therapeutics and Innovation in Oncology Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas., Srinivasan S; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas., Lang FF; Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas., Sulman EP; Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Lorenzi PL; Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Tan L; Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Shan M; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan., Tolstyka ZP; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan., Kachman M; Michigan Regional Comprehensive Metabolomics Resource Core, University of Michigan, Ann Arbor, Michigan., Zhang L; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan., Gao S; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas., Deem AK; The Translational Research to Advance Therapeutics and Innovation in Oncology Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas.; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas., Genovese G; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Scaglioni PP; Department of Internal Medicine Division of Hematology & Oncology, University of Cincinnati, Cincinnati, Ohio., Lyssiotis CA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan. GDraetta@mdanderson.org AViale@mdanderson.org FPuca@mdanderson.org CLyssiot@med.umich.edu.; Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan.; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan., Viale A; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. GDraetta@mdanderson.org AViale@mdanderson.org FPuca@mdanderson.org CLyssiot@med.umich.edu., Draetta GF; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. GDraetta@mdanderson.org AViale@mdanderson.org FPuca@mdanderson.org CLyssiot@med.umich.edu. |
المصدر: | Cancer discovery [Cancer Discov] 2021 Nov; Vol. 11 (11), pp. 2904-2923. Date of Electronic Publication: 2021 May 26. |
نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 101561693 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2159-8290 (Electronic) Linking ISSN: 21598274 NLM ISO Abbreviation: Cancer Discov Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: Philadelphia, PA : American Association for Cancer Research |
مواضيع طبية MeSH: | Acyl-CoA Dehydrogenase*/metabolism , Glioblastoma*/enzymology , Glioblastoma*/genetics , Lipid Peroxidation* , Mitochondria*/metabolism, Apoptosis ; Fatty Acids/metabolism ; Humans ; Oxidative Stress |
مستخلص: | Glioblastoma (GBM) is highly resistant to chemotherapies, immune-based therapies, and targeted inhibitors. To identify novel drug targets, we screened orthotopically implanted, patient-derived glioblastoma sphere-forming cells using an RNAi library to probe essential tumor cell metabolic programs. This identified high dependence on mitochondrial fatty acid metabolism. We focused on medium-chain acyl-CoA dehydrogenase (MCAD), which oxidizes medium-chain fatty acids (MCFA), due to its consistently high score and high expression among models and upregulation in GBM compared with normal brain. Beyond the expected energetics impairment, MCAD depletion in primary GBM models induced an irreversible cascade of detrimental metabolic effects characterized by accumulation of unmetabolized MCFAs, which induced lipid peroxidation and oxidative stress, irreversible mitochondrial damage, and apoptosis. Our data uncover a novel protective role for MCAD to clear lipid molecules that may cause lethal cell damage, suggesting that therapeutic targeting of MCFA catabolism may exploit a key metabolic feature of GBM. SIGNIFICANCE: MCAD exerts a protective role to prevent accumulation of toxic metabolic by-products in glioma cells, actively catabolizing lipid species that would otherwise affect mitochondrial integrity and induce cell death. This work represents a first demonstration of a nonenergetic role for dependence on fatty acid metabolism in cancer. This article is highlighted in the In This Issue feature, p. 2659 . (©2021 The Authors; Published by the American Association for Cancer Research.) |
References: | J Neurosci. 2014 Sep 3;34(36):11929-47. (PMID: 25186741) Cell Metab. 2020 Aug 4;32(2):229-242.e8. (PMID: 32559414) Cancers (Basel). 2013 Nov 08;5(4):1469-84. (PMID: 24217114) Circulation. 2012 Oct 2;126(14):1705-16. (PMID: 22932257) J Neurosurg. 2000 Feb;92(2):326-33. (PMID: 10659021) Biochemistry. 1991 Nov 5;30(44):10755-60. (PMID: 1931995) Biochem Biophys Res Commun. 1996 May 6;222(1):83-9. (PMID: 8630079) J Biochem. 1982 Oct;92(4):1109-21. (PMID: 7174640) Proc Natl Acad Sci U S A. 2011 Sep 20;108(38):16062-7. (PMID: 21900605) Neuro Oncol. 2017 Jan;19(1):43-54. (PMID: 27365097) J Mass Spectrom. 1996 Mar;31(3):255-62. (PMID: 8799277) Can J Biochem. 1969 May;47(5):493-9. (PMID: 5787689) Diabetes Obes Metab. 2014 Aug;16(8):757-60. (PMID: 24330405) J Neurochem. 2008 May;105(3):1019-31. (PMID: 18182042) Biochem Pharmacol. 2010 Mar 1;79(5):792-9. (PMID: 19854160) World J Gastroenterol. 2014 Oct 21;20(39):14205-18. (PMID: 25339807) Nat Rev Clin Oncol. 2017 Jul;14(7):434-452. (PMID: 28031556) Biochimie. 1996;78(3):155-64. (PMID: 8831946) Cell Rep. 2016 Jun 28;16(1):133-147. (PMID: 27320920) J Neurosci. 2003 Jul 2;23(13):5928-35. (PMID: 12843297) Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19345-50. (PMID: 18032601) Stem Cells. 2015 Aug;33(8):2400-15. (PMID: 25966666) Neurosurg Focus. 2006 Apr 15;20(4):E5. (PMID: 16709036) Neuro Oncol. 2018 Feb 19;20(3):380-390. (PMID: 29016843) Nat Rev Mol Cell Biol. 2019 Mar;20(3):137-155. (PMID: 30523332) PLoS Genet. 2005 Aug;1(2):e23. (PMID: 16121256) Cancer Res. 2005 Apr 15;65(8):3307-18. (PMID: 15833864) Lipids. 1987 Sep;22(9):627-36. (PMID: 3669925) Trends Cell Biol. 2016 Mar;26(3):165-176. (PMID: 26653790) J Lipid Res. 2003 Feb;44(2):388-98. (PMID: 12576521) Mol Genet Metab. 2010 Jul;100(3):241-50. (PMID: 20434380) Cell. 2013 Oct 10;155(2):462-77. (PMID: 24120142) Nat Rev Cancer. 2013 Apr;13(4):227-32. (PMID: 23446547) J Am Soc Nephrol. 2013 Jul;24(8):1250-61. (PMID: 23813215) Ann Neurosci. 2016 Mar;23(1):51-5. (PMID: 27536022) Cell Rep. 2016 Aug 9;16(6):1614-1628. (PMID: 27477280) Nature. 2018 Aug;560(7717):243-247. (PMID: 30069053) Nature. 2008 Oct 23;455(7216):1061-8. (PMID: 18772890) Stem Cells Int. 2016;2016:7849890. (PMID: 26880988) Cancer Lett. 2017 Sep 10;403:224-230. (PMID: 28649003) Pharmacol Res. 2000 Feb;41(2):143-50. (PMID: 10623482) Cell Death Discov. 2017 Sep 18;3:17063. (PMID: 28924490) J Neurosurg. 2018 Jan;128(1):287-295. (PMID: 28362237) Nat Methods. 2009 Aug;6(8):569-75. (PMID: 19644458) Acta Neuropathol. 2015 May;129(5):679-93. (PMID: 25783747) Nat Rev Clin Oncol. 2017 Nov;14(11):695-707. (PMID: 28675164) J Inherit Metab Dis. 2010 Oct;33(5):513-20. (PMID: 20532824) Annu Rev Nutr. 1985;5:365-90. (PMID: 2992549) Science. 1956 Feb 24;123(3191):309-14. (PMID: 13298683) J Neurochem. 1988 Feb;50(2):639-43. (PMID: 3335863) Chemotherapy. 2013;59(3):214-24. (PMID: 24356281) N Engl J Med. 2005 Mar 10;352(10):987-96. (PMID: 15758009) |
معلومات مُعتمدة: | P30 CA016672 United States CA NCI NIH HHS; R01 CA248160 United States CA NCI NIH HHS; R01 CA244931 United States CA NCI NIH HHS; U24 DK097153 United States DK NIDDK NIH HHS; P50 CA127001 United States CA NCI NIH HHS; R37 CA237421 United States CA NCI NIH HHS; P30 CA046592 United States CA NCI NIH HHS; R01 CA218139 United States CA NCI NIH HHS |
المشرفين على المادة: | 0 (Fatty Acids) EC 1.3.8.7 (Acyl-CoA Dehydrogenase) |
تواريخ الأحداث: | Date Created: 20210527 Date Completed: 20220316 Latest Revision: 20220531 |
رمز التحديث: | 20240628 |
مُعرف محوري في PubMed: | PMC8711129 |
DOI: | 10.1158/2159-8290.CD-20-1437 |
PMID: | 34039636 |
قاعدة البيانات: | MEDLINE |
تدمد: | 2159-8290 |
---|---|
DOI: | 10.1158/2159-8290.CD-20-1437 |