دورية أكاديمية
Autophagy sustains mitochondrial respiration and determines resistance to BRAF V600E inhibition in thyroid carcinoma cells.
| العنوان: | Autophagy sustains mitochondrial respiration and determines resistance to BRAF V600E inhibition in thyroid carcinoma cells. |
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| المؤلفون: | Díaz-Gago S; Universidad de Alcalá, Facultad de Medicina y Ciencias de la Salud, Departamento de Biología de Sistemas, Unidad de Bioquímica y Biología Molecular, Madrid, Spain., Vicente-Gutiérrez J; Universidad de Alcalá, Facultad de Medicina y Ciencias de la Salud, Departamento de Biología de Sistemas, Unidad de Bioquímica y Biología Molecular, Madrid, Spain., Ruiz-Rodríguez JM; Universidad de Alcalá, Facultad de Medicina y Ciencias de la Salud, Departamento de Biología de Sistemas, Unidad de Bioquímica y Biología Molecular, Madrid, Spain., Calafell J; Universidad de Alcalá, Facultad de Medicina y Ciencias de la Salud, Departamento de Biología de Sistemas, Unidad de Bioquímica y Biología Molecular, Madrid, Spain., Álvarez-Álvarez A; Universidad de Alcalá, Facultad de Medicina y Ciencias de la Salud, Departamento de Biología de Sistemas, Unidad de Bioquímica y Biología Molecular, Madrid, Spain., Lasa M; Departamento de Bioquímica-Instituto de Investigaciones Biomédicas Sols-Morreale, Universidad Autónoma de Madrid-Consejo Superior de Investigaciones Científicas, Madrid, Spain., Chiloeches A; Universidad de Alcalá, Facultad de Medicina y Ciencias de la Salud, Departamento de Biología de Sistemas, Unidad de Bioquímica y Biología Molecular, Madrid, Spain., Baquero P; Universidad de Alcalá, Facultad de Medicina y Ciencias de la Salud, Departamento de Biología de Sistemas, Unidad de Bioquímica y Biología Molecular, Madrid, Spain. |
| المصدر: | Autophagy [Autophagy] 2024 Jun; Vol. 20 (6), pp. 1383-1397. Date of Electronic Publication: 2024 Mar 04. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Taylor & Francis Country of Publication: United States NLM ID: 101265188 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1554-8635 (Electronic) Linking ISSN: 15548627 NLM ISO Abbreviation: Autophagy Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2015- : Philadelphia, PA : Taylor & Francis Original Publication: Georgetown, TX : Landes Bioscience, 2005- |
| مواضيع طبية MeSH: | Autophagy*/drug effects , Autophagy*/genetics , Thyroid Neoplasms*/pathology , Thyroid Neoplasms*/genetics , Thyroid Neoplasms*/metabolism , Mitochondria*/metabolism , Mitochondria*/drug effects , Proto-Oncogene Proteins B-raf*/metabolism , Proto-Oncogene Proteins B-raf*/genetics , Drug Resistance, Neoplasm*/drug effects , Drug Resistance, Neoplasm*/genetics, Humans ; Cell Line, Tumor ; Fatty Acids/metabolism ; Glycolysis/drug effects ; Proto-Oncogene Mas ; Vemurafenib/pharmacology ; Lipolysis/drug effects ; Cell Respiration/drug effects ; Autophagy-Related Protein 7/metabolism ; Autophagy-Related Protein 7/genetics ; Sulfonamides/pharmacology ; Oxidative Phosphorylation/drug effects ; Lysosomes/metabolism ; Lysosomes/drug effects ; Indoles/pharmacology |
| مستخلص: | BRAF V600E is the most prevalent mutation in thyroid cancer and correlates with poor prognosis and therapy resistance. Although selective inhibitors of BRAF V600E have been developed, more advanced tumors such as anaplastic thyroid carcinomas show a poor response in clinical trials. Therefore, the study of alternative survival mechanisms is needed. Since metabolic changes have been related to malignant progression, in this work we explore metabolic dependencies of thyroid tumor cells to exploit them therapeutically. Our results show that respiration of thyroid carcinoma cells is highly dependent on fatty acid oxidation and, in turn, fatty acid mitochondrial availability is regulated through macroautophagy/autophagy. Furthermore, we show that both lysosomal inhibition and the knockout of the essential autophagy gene, ATG7 , lead to enhanced lipolysis; although this effect is not essential for survival of thyroid carcinoma cells. We also demonstrate that following inhibition of either autophagy or fatty acid oxidation, thyroid tumor cells compensate oxidative phosphorylation deficiency with an increase in glycolysis. In contrast to lipolysis induction, upon autophagy inhibition, glycolytic boost in autophagy-deficient cells is essential for survival and, importantly, correlates with a higher sensitivity to the BRAF V600E selective inhibitor, vemurafenib. In agreement, downregulation of the glycolytic pathway results in enhanced mitochondrial respiration and vemurafenib resistance. Our work provides new insights into the role of autophagy in thyroid cancer metabolism and supports mitochondrial targeting in combination with vemurafenib to eliminate BRAF V600E -positive thyroid carcinoma cells. Abbreviations : AMP: adenosine monophosphate; ATC: anaplastic thyroid carcinoma; ATG: autophagy related; ATP: adenosine triphosphate; BRAF: B-Raf proto-oncogene, serine/threonine kinase; Cas9: CRISPR-associated protein; CREB: cAMP responsive element binding protein; CRISPR: clustered regularly interspaced short palindromic repeats; 2DG: 2-deoxyglucose; FA: fatty acid; FAO: fatty acid oxidation; FASN: fatty acid synthase; FCCP: trifluoromethoxy carbonyl cyanide phenylhydrazone; LAMP1: lysosomal associated membrane protein 1; LIPE/HSL: lipase E, hormone sensitive type; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; OCR: oxygen consumption rate; OXPHOS: oxidative phosphorylation; PRKA/PKA: protein kinase cAMP-activated; PTC: papillary thyroid carcinoma; SREBF1/SREBP1: sterol regulatory element binding transcription factor 1. |
| References: | Front Oncol. 2022 Jul 14;12:952371. (PMID: 35912181) EMBO J. 2008 Jan 23;27(2):433-46. (PMID: 18200046) Autophagy. 2014 Aug;10(8):1391-402. (PMID: 24991838) JAMA Oncol. 2020 Sep 1;6(9):1397-1404. (PMID: 32761153) Cancer Lett. 2013 Jul 10;335(1):232-41. (PMID: 23435375) Genes Dev. 2019 Feb 1;33(3-4):150-165. (PMID: 30692209) Nat Methods. 2014 Aug;11(8):783-784. (PMID: 25075903) Nature. 2010 Sep 30;467(7315):596-9. (PMID: 20823850) Mol Cancer Ther. 2016 Dec;15(12):2987-2999. (PMID: 27765851) Nat Rev Cancer. 2021 Dec;21(12):753-766. (PMID: 34417571) Nat Rev Cancer. 2012 Oct;12(10):685-98. (PMID: 23001348) Autophagy. 2015;11(7):1181-3. (PMID: 26046386) Cancer Discov. 2013 Nov;3(11):1272-85. (PMID: 23965987) J Gen Physiol. 1927 Mar 7;8(6):519-30. (PMID: 19872213) Autophagy. 2014 Aug;10(8):1359-68. (PMID: 24991840) Oncogene. 2005 Sep 29;24(43):6465-81. (PMID: 16007182) Front Cell Dev Biol. 2019 Sep 10;7:185. (PMID: 31552248) Autophagy. 2018;14(4):671-684. (PMID: 28980855) Ann Oncol. 2022 Apr;33(4):406-415. (PMID: 35026411) J Clin Endocrinol Metab. 2003 Nov;88(11):5399-404. (PMID: 14602780) Science. 2014 Jan 3;343(6166):84-87. (PMID: 24336571) J Biol Chem. 1998 Jan 2;273(1):215-21. (PMID: 9417067) Endocr Rev. 2007 Dec;28(7):742-62. (PMID: 17940185) Clin Cancer Res. 2022 Mar 15;28(6):1098-1106. (PMID: 35022320) Nat Rev Drug Discov. 2022 Feb;21(2):141-162. (PMID: 34862480) Nat Rev Mol Cell Biol. 2018 Jun;19(6):349-364. (PMID: 29618831) Autophagy. 2014 Aug;10(8):1369-79. (PMID: 24991839) Cell Metab. 2017 May 2;25(5):1037-1043. (PMID: 28467923) Cancer Discov. 2014 Apr;4(4):423-33. (PMID: 24469106) Science. 2009 Sep 18;325(5947):1555-9. (PMID: 19661383) Autophagy. 2013 Oct;9(10):1636-8. (PMID: 23959381) Nature. 2009 Apr 30;458(7242):1131-5. (PMID: 19339967) Genes Dev. 2013 Jul 1;27(13):1447-61. (PMID: 23824538) N Engl J Med. 2016 Dec 8;375(23):2307. (PMID: 27959677) N Engl J Med. 2015 Aug 20;373(8):726-36. (PMID: 26287849) Blood. 2004 Jan 15;103(2):580-2. (PMID: 14512303) Thyroid. 2021 Sep;31(9):1335-1358. (PMID: 33107403) Autophagy. 2023 Feb;19(2):720-723. (PMID: 35799322) Surgery. 2013 Dec;154(6):1436-46; discussion 1446-7. (PMID: 24075674) Cancer Cell. 2013 Mar 18;23(3):302-15. (PMID: 23477830) Proc Natl Acad Sci U S A. 2013 Nov 5;110(45):18226-31. (PMID: 24145418) Apoptosis. 2020 Dec;25(11-12):835-852. (PMID: 32955614) J Clin Endocrinol Metab. 2003 Sep;88(9):4393-7. (PMID: 12970315) |
| فهرسة مساهمة: | Keywords: Cancer metabolism; fatty acid oxidation; glycolysis; oxidative phosphorylation; thyroid cancer; vemurafenib resistance |
| المشرفين على المادة: | EC 2.7.11.1 (Proto-Oncogene Proteins B-raf) 0 (MAS1 protein, human) 0 (Fatty Acids) 0 (Proto-Oncogene Mas) 207SMY3FQT (Vemurafenib) EC 6.2.1.45 (Autophagy-Related Protein 7) 0 (Sulfonamides) EC 2.7.11.1 (BRAF protein, human) EC 6.2.1.45 (ATG7 protein, human) 0 (Indoles) |
| تواريخ الأحداث: | Date Created: 20240304 Date Completed: 20240621 Latest Revision: 20240630 |
| رمز التحديث: | 20240630 |
| مُعرف محوري في PubMed: | PMC11210916 |
| DOI: | 10.1080/15548627.2024.2312790 |
| PMID: | 38436206 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 1554-8635 |
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| DOI: | 10.1080/15548627.2024.2312790 |