Reference : Severe metabolic alterations in liver cancer lead to ERK pathway activation and drug ...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Systems Biomedicine
http://hdl.handle.net/10993/44352
Severe metabolic alterations in liver cancer lead to ERK pathway activation and drug resistance
English
Nwosu, Zeribe Chike [Department of Medicine II, Molecular Hepatology Section, Medical Faculty Mannheim, University of Heidelberg, Germany.]
Piorońska, Weronika [Department of Medicine II, Molecular Hepatology Section, Medical Faculty Mannheim, University of Heidelberg, Germany]
Battello, Nadia [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Zimmer, Andreas David [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
Dewidar, Bedair [Department of Medicine II, Molecular Hepatology Section, Medical Faculty Mannheim, University of Heidelberg, Germany]
Han, Mei [Department of Medicine II, Molecular Hepatology Section, Medical Faculty Mannheim, University of Heidelberg,Germany.]
Pereira, Sharon [Department of Medicine I, Lichtenberg Research Group, Johannes Gutenberg University, Mainz, Germany.]
Blagojevic, Biljana [Department of Biology, Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Germany.]
Castven, Darko [Department of Medicine I, Lichtenberg Research Group, Johannes Gutenberg University, Mainz, Germany.]
Charlestin, Verodia [Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, United States.]
Holenya, Pavlo [Department of Biology, Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Germany.]
Lochead, Julia [Department of Biology, Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Germany]
De La Torre, Carolina [Medical Research Center, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany]
Gretz, Norbert [Medical Research Center, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany]
Sajjakulnukit, Peter [Rogel Cancer Center, University of Michigan, United States.]
Zhang, Li [Rogel Cancer Center, University of Michigan, United States.]
Ward, Matthew H [Rogel Cancer Center, University of Michigan, United States.]
Marquardt, Jens U [Department of Medicine I, Lichtenberg Research Group, Johannes Gutenberg University, Mainz, Germany]
Pasca di Magliano, Marina [Medical Research Center, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany]
Lyssiotis, Costas A [Rogel Cancer Center, University of Michigan, United States]
Sleeman, Jonathan [Medical Faculty Mannheim, ECAS TRIDOMUS-Gebäude Haus C, University of Heidelberg, Germany]
Wölfl, Stefan [Department of Biology, Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Germany.]
Ebert, Matthias Philip [Department of Medicine II, Molecular Hepatology Section, Medical Faculty Mannheim, University of Heidelberg, Germany.]
Meyer, Christoph [Department of Medicine II, Molecular Hepatology Section, Medical Faculty Mannheim, University of Heidelberg, Germany]
Hofmann, Ute [Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tübingen, Germany.]
Dooley, Steven [Department of Medicine II, Molecular Hepatology Section, Medical Faculty Mannheim, University of Heidelberg,Germany.]
Apr-2020
EBioMedicine
Elsevier
Yes (verified by ORBilu)
International
2352-3964
Amsterdam
Netherlands
[en] Aerobic glycolysis ; Glutamine ; Kinase inhibitors ; HCC ; Proliferation ; Serine
[en] 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.
DFG, BMBF and Sino-German Cooperation Project
http://hdl.handle.net/10993/44352
10.1016/j.ebiom.2020.102699

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