[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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
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.
