دورية أكاديمية
Mitotane Targets Lipid Droplets to Induce Lipolysis in Adrenocortical Carcinoma.
| العنوان: | Mitotane Targets Lipid Droplets to Induce Lipolysis in Adrenocortical Carcinoma. |
|---|---|
| المؤلفون: | Warde KM; Discipline of Pharmacology and Therapeutics, National University of Ireland, Galway, H91 TK33, Ireland., Lim YJ; Discipline of Pharmacology and Therapeutics, National University of Ireland, Galway, H91 TK33, Ireland., Ribes Martinez E; Discipline of Pharmacology and Therapeutics, National University of Ireland, Galway, H91 TK33, Ireland., Beuschlein F; Department of Medicine IV, University Hospital, Ludwig Maximilian University of Munich, Munich, 81377, Germany.; Department of Endocrinology, Diabetes, and Clinical Nutrition, University Hospital Zurich, Zurich 8091, Switzerland., O'Shea P; Department of Clinical Biochemistry, Galway University Hospitals, Saolta Hospitals Group, Newcastle Road, Galway, H91 RW28, Ireland., Hantel C; Department of Medicine IV, University Hospital, Ludwig Maximilian University of Munich, Munich, 81377, Germany.; Medizinische Klinik und Poliklinik III, University Hospital Carl Gustav Carus Dresden, 01307, Germany., Dennedy MC; Discipline of Pharmacology and Therapeutics, National University of Ireland, Galway, H91 TK33, Ireland. |
| المصدر: | Endocrinology [Endocrinology] 2022 Sep 01; Vol. 163 (9). |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Oxford University Press Country of Publication: United States NLM ID: 0375040 Publication Model: Print Cited Medium: Internet ISSN: 1945-7170 (Electronic) Linking ISSN: 00137227 NLM ISO Abbreviation: Endocrinology Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2017- : New York : Oxford University Press Original Publication: Los Angeles, Calif. : Association for the Study of Internal Secretions, |
| مواضيع طبية MeSH: | Adrenal Cortex Neoplasms*/metabolism , Adrenocortical Carcinoma*/metabolism, Antineoplastic Agents, Hormonal/pharmacology ; Antineoplastic Agents, Hormonal/therapeutic use ; Cell Line, Tumor ; Cholesterol/metabolism ; Humans ; Lipid Droplets/metabolism ; Lipolysis ; Mitotane/metabolism ; Mitotane/pharmacology ; Mitotane/therapeutic use |
| مستخلص: | Introduction: Adrenocortical carcinoma (ACC) is a rare aggressive cancer with low overall survival. Adjuvant mitotane improves survival but is limited by poor response rates and resistance. Mitotane's efficacy is attributed to the accumulation of toxic free cholesterol, predominantly through cholesterol storage inhibition. However, targeting this pathway has proven unsuccessful. We hypothesize that mitotane-induced free-cholesterol accumulation is also mediated through enhanced breakdown of lipid droplets. Methodology: ATCC-H295R (mitotane-sensitive) and MUC-1 (mitotane-resistant) ACC cells were evaluated for lipid content using specific BODIPY dyes. Protein expression was evaluated by immunoblotting and flow cytometry. Cell viability was measured by quantifying propidium iodide-positive cells following mitotane treatment and pharmacological inhibitors of lipolysis. Results: H295R and MUC-1 cells demonstrated similar neutral lipid droplet numbers at baseline. However, evaluation of lipid machinery demonstrated distinct profiles in each model. Analysis of intracellular lipid droplet content showed H295R cells preferentially store cholesteryl esters, whereas MUC-1 cells store triacylglycerol. Decreased lipid droplets were associated with increased lipolysis in H295R and in MUC-1 at toxic mitotane concentrations. Pharmacological inhibition of lipolysis attenuated mitotane-induced toxicity in both models. Conclusion: We highlight that lipid droplet breakdown and activation of lipolysis represent a putative additional mechanism for mitotane-induced cytotoxicity in ACC. Further understanding of cholesterol and lipids in ACC offers potential novel therapeutic exploitation, especially in mitotane-resistant disease. (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.) |
| التعليقات: | Comment in: Endocrinology. 2023 Jan 9;164(3):. (PMID: 36636840) |
| References: | J Biol Chem. 1993 Jun 5;268(16):11811-6. (PMID: 7685021) J Lipid Res. 2008 Apr;49(4):738-45. (PMID: 18204096) Invest New Drugs. 2020 Oct;38(5):1421-1429. (PMID: 31984451) Int J Endocrinol. 2013;2013:624962. (PMID: 24348556) Nature. 1990 Feb 1;343(6257):425-30. (PMID: 1967820) Oncotarget. 2016 Nov 29;7(48):79292-79304. (PMID: 27764813) Cancer Res. 2020 Nov 15;80(22):4932-4945. (PMID: 32816911) J Clin Endocrinol Metab. 2017 Apr 01;102(4):1358-1365. (PMID: 28324035) Endocrinology. 2016 May;157(5):1775-88. (PMID: 26986192) Nat Immunol. 2020 Nov;21(11):1444-1455. (PMID: 32958928) Nat Genet. 2014 Jun;46(6):607-12. (PMID: 24747642) J Biol Chem. 1999 Jan 1;274(1):41-7. (PMID: 9867808) Mol Cell Endocrinol. 2013 Dec 5;381(1-2):66-9. (PMID: 23906534) Cancer. 2008 Dec 1;113(11):3130-6. (PMID: 18973179) N Engl J Med. 2007 Jun 7;356(23):2372-80. (PMID: 17554118) Mol Cell Endocrinol. 2007 Feb;265-266:42-5. (PMID: 17208360) Endocrinol Diabetes Metab Case Rep. 2016;2016:150135. (PMID: 27298727) J Cell Sci. 2012 Sep 1;125(Pt 17):4067-76. (PMID: 22685330) Oncogene. 2021 Jan;40(1):215-231. (PMID: 33110235) Cell Metab. 2014 Mar 4;19(3):393-406. (PMID: 24606897) Am J Physiol Endocrinol Metab. 2007 Feb;292(2):E408-12. (PMID: 16985254) Endocrinology. 2002 Mar;143(3):801-6. (PMID: 11861500) J Lipid Res. 2009 Nov;50(11):2306-13. (PMID: 19515989) Nat Commun. 2018 Jan 22;9(1):322. (PMID: 29358673) J Proteome Res. 2018 Apr 6;17(4):1415-1425. (PMID: 29457907) Nat Med. 2011 Oct 30;17(11):1498-503. (PMID: 22037646) Clin Cancer Res. 2019 Jun 1;25(11):3276-3288. (PMID: 30770352) Mol Endocrinol. 2004 Mar;18(3):549-57. (PMID: 14657254) J Clin Invest. 2006 Jul;116(7):1902-12. (PMID: 16823488) J Clin Endocrinol Metab. 2015 Aug;100(8):2890-8. (PMID: 26120791) Endocr Relat Cancer. 2020 Jun;27(6):361-373. (PMID: 32276262) J Clin Invest. 1996 Jun 1;97(11):2660-71. (PMID: 8647961) Oncotarget. 2015 Sep 29;6(29):28282-95. (PMID: 26318046) Front Endocrinol (Lausanne). 2021 Apr 26;12:669426. (PMID: 33981288) Mol Cell Endocrinol. 2017 Feb 5;441:17-21. (PMID: 27477781) Endocr Relat Cancer. 2008 Dec;15(4):1043-53. (PMID: 18824557) Eur J Endocrinol. 2021 May 04;184(6):823-835. (PMID: 33830941) Clin Cancer Res. 2016 Nov 1;22(21):5337-5348. (PMID: 27281560) Mol Cancer Ther. 2020 Sep;19(9):1909-1921. (PMID: 32546662) J Lipid Res. 1978 Jul;19(5):570-7. (PMID: 209112) Elife. 2017 Dec 19;6:. (PMID: 29256392) PLoS One. 2015 Jun 10;10(6):e0128903. (PMID: 26061292) Cancer Cell. 2016 Aug 8;30(2):363. (PMID: 27505681) Cell Metab. 2010 Mar 3;11(3):194-205. (PMID: 20197052) Endocr Relat Cancer. 2018 Apr;25(4):437-451. (PMID: 29371329) Endocrinology. 2015 Nov;156(11):3895-908. (PMID: 26305886) Clin Cancer Res. 2021 Dec 1;27(23):6432-6444. (PMID: 34518309) J Biol Chem. 2001 Nov 30;276(48):45456-61. (PMID: 11581251) Prog Lipid Res. 2011 Jan;50(1):14-27. (PMID: 21087632) Br J Cancer. 2020 Jan;122(2):209-220. (PMID: 31819189) Ann Oncol. 2015 Oct;26(10):2119-25. (PMID: 26392430) Ann Surg Oncol. 2016 Jan;23(1):134-41. (PMID: 26286195) Bio Protoc. 2016 Sep 5;6(17):. (PMID: 28573161) Eur J Endocrinol. 2013 Jul 29;169(3):263-70. (PMID: 23704714) Annu Rev Nutr. 2016 Jul 17;36:471-509. (PMID: 27431369) Eur J Endocrinol. 2016 Mar;174(3):343-53. (PMID: 26671975) Curr Opin Endocr Metab Res. 2019 Oct;8:139-144. (PMID: 32550272) Oncotarget. 2017 Jul 4;8(66):109924-109940. (PMID: 29299119) |
| فهرسة مساهمة: | Keywords: adrenocortical carcinoma; cholesterol; lipid droplets; lipolysis; mitotane; tumor resistance |
| المشرفين على المادة: | 0 (Antineoplastic Agents, Hormonal) 78E4J5IB5J (Mitotane) 97C5T2UQ7J (Cholesterol) |
| تواريخ الأحداث: | Date Created: 20220707 Date Completed: 20220803 Latest Revision: 20230113 |
| رمز التحديث: | 20240829 |
| مُعرف محوري في PubMed: | PMC9342684 |
| DOI: | 10.1210/endocr/bqac102 |
| PMID: | 35797592 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1945-7170 |
|---|---|
| DOI: | 10.1210/endocr/bqac102 |