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Verfasst von:Nwosu, Zeribe C. [VerfasserIn]   i
 Piorońska, Weronika [VerfasserIn]   i
 Battello, Nadia [VerfasserIn]   i
 Zimmer, Andreas David [VerfasserIn]   i
 Dewidar, Bedair [VerfasserIn]   i
 Han, Mei [VerfasserIn]   i
 Pereira, Sharon [VerfasserIn]   i
 Blagojević, Biljana [VerfasserIn]   i
 Castven, Darko [VerfasserIn]   i
 Charlestin, Verodia [VerfasserIn]   i
 Holenya, Pavlo [VerfasserIn]   i
 Lochead, Julia [VerfasserIn]   i
 Torre, Carolina de la [VerfasserIn]   i
 Gretz, Norbert [VerfasserIn]   i
 Sajjakulnukit, Peter [VerfasserIn]   i
 Zhang, Li [VerfasserIn]   i
 Ward, Matthew H. [VerfasserIn]   i
 Marquardt, Jens [VerfasserIn]   i
 di Magliano, Marina Pasca [VerfasserIn]   i
 Lyssiotis, Costas A. [VerfasserIn]   i
 Sleeman, Jonathan P. [VerfasserIn]   i
 Wölfl, Stefan [VerfasserIn]   i
 Ebert, Matthias [VerfasserIn]   i
 Meyer, Christoph [VerfasserIn]   i
 Hofmann, Ute [VerfasserIn]   i
 Dooley, Steven [VerfasserIn]   i
Titel:Severe metabolic alterations in liver cancer lead to ERK pathway activation and drug resistance
Verf.angabe:Zeribe Chike Nwosu, Weronika Piorońska, Nadia Battello, Andreas David Zimmer, Bedair Dewidar, Mei Han, Sharon Pereira, Biljana Blagojevic, Darko Castven, Verodia Charlestin, Pavlo Holenya, Julia Lochead, Carolina De La Torre, Norbert Gretz, Peter Sajjakulnukit, Li Zhang, Matthew H. Ward, Jens U. Marquardt, Marina Pasca di Magliano, Costas A. Lyssiotis, Jonathan Sleeman, Stefan Wölfl, Matthias Philip Ebert, Christoph Meyer, Ute Hofmann, Steven Dooley
E-Jahr:2020
Jahr:21 April 2020
Umfang:14 S.
Fussnoten:Gesehen am 02.07.2020
Titel Quelle:Enthalten in: EBioMedicine
Ort Quelle:Amsterdam [u.a.] : Elsevier, 2014
Jahr Quelle:2020
Band/Heft Quelle:54(2020) Artikel-Nummer 102699, 14 Seiten
ISSN Quelle:2352-3964
Abstract:Background - The extracellular signal-regulated kinase (ERK) pathway regulates cell growth, and is hyper-activated and associated with drug resistance in hepatocellular carcinoma (HCC). Metabolic pathways are profoundly dysregulated in HCC. Whether an altered metabolic state is linked to activated ERK pathway and drug response in HCC is unaddressed. - Methods - We deprived HCC cells of glutamine to induce metabolic alterations and performed various assays, including metabolomics (with 13C-glucose isotope tracing), microarray analysis, and cell proliferation assays. Glutamine-deprived cells were also treated with kinase inhibitors (e.g. Sorafenib, Erlotinib, U0126 amongst other MEK inhibitors). We performed bioinformatics analysis and stratification of HCC tumour microarrays to determine upregulated ERK gene signatures in patients. - Findings - In a subset of HCC cells, the withdrawal of glutamine triggers a severe metabolic alteration and ERK phosphorylation (pERK). This is accompanied by resistance to the anti-proliferative effect of kinase inhibitors, despite pERK inhibition. High intracellular serine is a consistent feature of an altered metabolic state and contributes to pERK induction and the kinase inhibitor resistance. Blocking the ERK pathway facilitates cell proliferation by reprogramming metabolism, notably enhancing aerobic glycolysis. We have identified 24 highly expressed ERK gene signatures that their combined expression strongly indicates a dysregulated metabolic gene network in human HCC tissues. - Interpretation - A severely compromised metabolism lead to ERK pathway induction, and primes some HCC cells to pro-survival phenotypes upon ERK pathway blockade. Our findings offer novel insights for understanding, predicting and overcoming drug resistance in liver cancer patients. - Fund - DFG, BMBF and Sino-German Cooperation Project
DOI:doi:10.1016/j.ebiom.2020.102699
URL:Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.

Volltext: https://doi.org/10.1016/j.ebiom.2020.102699
 Volltext: http://www.sciencedirect.com/science/article/pii/S2352396420300748
 DOI: https://doi.org/10.1016/j.ebiom.2020.102699
Datenträger:Online-Ressource
Sprache:eng
Sach-SW:Aerobic glycolysis
 Glutamine
 HCC
 Kinase inhibitors
 Metabolic state
 Proliferation
 Serine
K10plus-PPN:1703311345
Verknüpfungen:→ Zeitschrift

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