دورية أكاديمية
Membrane disruption, but not metabolic rewiring, is the key mechanism of anticancer-action of FASN-inhibitors: a multi-omics analysis in ovarian cancer.
| العنوان: | Membrane disruption, but not metabolic rewiring, is the key mechanism of anticancer-action of FASN-inhibitors: a multi-omics analysis in ovarian cancer. |
|---|---|
| المؤلفون: | Grunt, Thomas W, Slany, Astrid, Semkova, Mariya, López-Rodríguez, María Luz, Wuczkowski, Michael, Wagner, Renate, Gerner, Christopher, Stübiger, Gerald, Colomer, Ramón |
| المساهمون: | Kinexus Bioinformatics Corporation (Canadá), Medical Scientific Fund of the Mayor of the City of Vienna, Medical University of Vienna (Austria) |
| بيانات النشر: | Nature Publishing Group |
| سنة النشر: | 2020 |
| المجموعة: | REPISALUD (REPositorio Institucional en SALUD del Instituto de Salud Carlos III - ISCIII) |
| الوصف: | Fatty-acid(FA)-synthase(FASN) is a druggable lipogenic oncoprotein whose blockade causes metabolic disruption. Whether drug-induced metabolic perturbation is essential for anticancer drug-action, or is just a secondary-maybe even a defence response-is still unclear. To address this, SKOV3 and OVCAR3 ovarian cancer(OC) cell lines with clear cell and serous histology, two main OC subtypes, were exposed to FASN-inhibitor G28UCM. Growth-inhibition was compared with treatment-induced cell-metabolomes, lipidomes, proteomes and kinomes. SKOV3 and OVCAR3 were equally sensitive to low-dose G28UCM, but SKOV3 was more resistant than OVCAR3 to higher concentrations. Metabolite levels generally decreased upon treatment, but individual acylcarnitines, glycerophospholipids, sphingolipids, amino-acids, biogenic amines, and monosaccharides reacted differently. Drug-induced effects on central-carbon-metabolism and oxidative-phosphorylation (OXPHOS) were essentially different in the two cell lines, since drug-naïve SKOV3 are known to prefer glycolysis, while OVCAR3 favour OXPHOS. Moreover, drug-dependent increase of desaturases and polyunsaturated-fatty-acids (PUFAs) were more pronounced in SKOV3 and appear to correlate with G28UCM-tolerance. In contrast, expression and phosphorylation of proteins that control apoptosis, FA synthesis and membrane-related processes (beta-oxidation, membrane-maintenance, transport, translation, signalling and stress-response) were concordantly affected. Overall, membrane-disruption and second-messenger-silencing were crucial for anticancer drug-action, while metabolic-rewiring was only secondary and may support high-dose-FASN-inhibitor-tolerance. These findings may guide future anti-metabolic cancer intervention. ; The authors would like to thank Kratos/Shimadzu (Manchester, UK) for providing the MALDI-MS instrumentation used in this study and Dr. Steven Pelech (Kinexus Bioinformatics Corp, Vancouver, BC, Canada) for initial instruction in antibody microarray kinomic analysis. This work was ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 2045-2322 |
| العلاقة: | Publisher's version; https://doi.org/10.1038/s41598-020-71491-zTest.; Sci Rep . 2020 ;10(1):14877.; http://hdl.handle.net/20.500.12105/11094Test; Scientific reports |
| DOI: | 10.1038/s41598-020-71491-z |
| الإتاحة: | https://doi.org/20.500.12105/11094Test https://doi.org/10.1038/s41598-020-71491-zTest https://hdl.handle.net/20.500.12105/11094Test |
| حقوق: | http://creativecommons.org/licenses/by-nc-sa/4.0Test/ ; Atribución-NoComercial-CompartirIgual 4.0 Internacional ; info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.6B34D7DC |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 20452322 |
|---|---|
| DOI: | 10.1038/s41598-020-71491-z |