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Severe metabolic alterations in liver cancer lead to ERK pathway activation and drug resistance by Nwosu, Zeribe Chike; PioroÅska, Weronika; Battello, Nadia; Zimmer, Andreas David; Dewidar, Bedair; Han, Mei; Pereira, Sharon; Blagojevic, Biljana; Castven, Darko; Charlestin, Verodia; Holenya, Pavlo; Lochead, Julia; De La Torre, Carolina; Gretz, Norbert; Sajjakulnukit, Peter; Zhang, Li; Ward, Matthew H.; Marquardt, Jens U.; di Magliano, Marina Pasca; Lyssiotis, Costas A.; Sleeman, Jonathan; Wölfl, Stefan; Ebert, Matthias Philip; Meyer, Christoph; Hofmann, Ute; Dooley, Steven is a Medicine article available to read on EtoBox.

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## 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 ^13^C-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 p

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Author

Nwosu, Zeribe Chike; PioroÅska, Weronika; Battello, Nadia; Zimmer, Andreas David; Dewidar, Bedair; Han, Mei; Pereira, Sharon; Blagojevic, Biljana; Castven, Darko; Charlestin, Verodia; Holenya, Pavlo; Lochead, Julia; De La Torre, Carolina; Gretz, Norbert; Sajjakulnukit, Peter; Zhang, Li; Ward, Matthew H.; Marquardt, Jens U.; di Magliano, Marina Pasca; Lyssiotis, Costas A.; Sleeman, Jonathan; Wölfl, Stefan; Ebert, Matthias Philip; Meyer, Christoph; Hofmann, Ute; Dooley, Steven

Publisher

Elsevier ; Elsevier BV; Amsterdam: Elsevier (ISSN 2352-3964)

Published

2020

Language

EN

Field

Medicine (Life Sciences)