TY - JOUR
T1 - Severe metabolic alterations in liver cancer lead to ERK pathway activation and drug resistance
AU - Nwosu, Zeribe Chike
AU - Piorońska, Weronika
AU - Battello, Nadia
AU - Zimmer, Andreas David
AU - Dewidar, Bedair
AU - Han, Mei
AU - Pereira, Sharon
AU - Blagojevic, Biljana
AU - Castven, Darko
AU - Charlestin, Verodia
AU - Holenya, Pavlo
AU - Lochead, Julia
AU - De La Torre, Carolina
AU - Gretz, Norbert
AU - Sajjakulnukit, Peter
AU - Zhang, Li
AU - Ward, Matthew H.
AU - Marquardt, Jens U.
AU - di Magliano, Marina Pasca
AU - Lyssiotis, Costas A.
AU - Sleeman, Jonathan
AU - Wölfl, Stefan
AU - Ebert, Matthias Philip
AU - Meyer, Christoph
AU - Hofmann, Ute
AU - Dooley, Steven
N1 - Funding Information:
SD lab is supported by funds from the DFG ( Do373/13 – 1 ), BMBF program LiSyM (Grant PTJ-FKZ: 031 L0043 ) and the Sino-German Cooperation project ( GZ126 ) through the Sino-German Scientific centre . Part of this work was supported through Research grant (Stiftungsmittel: “Krebs-und Scharlachforschung”) to ZCN from the Medical Faculty Heidelberg, University of Heidelberg, Germany. CM is supported by a grant from the Deutsche Forschungsgemeinschaft (DFG) ( Me4532/1 – 1 ). UH is supported by the Federal Ministry of Education and Research (Germany) within the research network Systems Medicine of the Liver (LiSyM) grant 031L0037 and from the Robert-Bosch Foundation (Stuttgart, Germany). The funding bodies did not influence the content of this article.
Publisher Copyright:
© 2020 The Author(s)
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/4
Y1 - 2020/4
N2 - 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
AB - 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
UR - http://www.scopus.com/inward/record.url?scp=85083436611&partnerID=8YFLogxK
U2 - 10.1016/j.ebiom.2020.102699
DO - 10.1016/j.ebiom.2020.102699
M3 - Journal articles
C2 - 32330875
AN - SCOPUS:85083436611
SN - 2352-3964
VL - 54
JO - EBioMedicine
JF - EBioMedicine
M1 - 102699
ER -
