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Severe metabolic alterations in liver cancer lead to ERK pathway activation and drug resistance.

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.

SUBMITTER: Nwosu ZC

PROVIDER: S-EPMC7182727 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Severe metabolic alterations in liver cancer lead to ERK pathway activation and drug resistance.

Nwosu Zeribe Chike ZC Piorońska Weronika W Battello Nadia N Zimmer Andreas David AD Dewidar Bedair B Han Mei M Pereira Sharon S Blagojevic Biljana B Castven Darko D Charlestin Verodia V Holenya Pavlo P Lochead Julia J De La Torre Carolina C Gretz Norbert N Sajjakulnukit Peter P Zhang Li L Ward Matthew H MH Marquardt Jens U JU di Magliano Marina Pasca MP Lyssiotis Costas A CA Sleeman Jonathan J Wölfl Stefan S Ebert Matthias Philip MP Meyer Christoph C Hofmann Ute U Dooley Steven S

EBioMedicine 20200421

<h4>Background</h4>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.<h4>Methods</h4>We deprived HCC cells of glutamine to induce metabolic alterations and performed various assays, including metabolomics (with < ...[more]

PMID: 32330875

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Project description:BackgroundDiscovery and development of novel drugs that are capable of overcoming drug resistance in tumor cells are urgently needed clinically. In this study, we sought to explore whether ivermectin (IVM), a macrolide antiparasitic agent, could overcome the resistance of cancer cells to the therapeutic drugs.MethodsWe used two solid tumor cell lines (HCT-8 colorectal cancer cells and MCF-7 breast cancer cells) and one hematologic tumor cell line (K562 chronic myeloid leukemia cells), which are resistant to the chemotherapeutic drugs vincristine and adriamycin respectively, and two xenograft mice models, including the solid tumor model in nude mice with the resistant HCT-8 cells and the leukemia model in NOD/SCID mice with the resistant K562 cells to investigate the reversal effect of IVM on the resistance in vitro and in vivo. MTT assay was used to investigate the effect of IVM on cancer cells growth in vitro. Flow cytometry, immunohistochemistry, and immunofluorescence were performed to investigate the reversal effect of IVM in vivo. Western blotting, qPCR, luciferase reporter assay and ChIP assay were used to detect the molecular mechanism of the reversal effect. Octet RED96 system and Co-IP were used to determine the interactions between IVM and EGFR.ResultsOur results indicated that ivermectin at its very low dose, which did not induce obvious cytotoxicity, drastically reversed the resistance of the tumor cells to the chemotherapeutic drugs both in vitro and in vivo. Mechanistically, ivermectin reversed the resistance mainly by reducing the expression of P-glycoprotein (P-gp) via inhibiting the epidermal growth factor receptor (EGFR), not by directly inhibiting P-gp activity. Ivermectin bound with the extracellular domain of EGFR, which inhibited the activation of EGFR and its downstream signaling cascade ERK/Akt/NF-?B. The inhibition of the transcriptional factor NF-?B led to the reduced P-gp transcription.ConclusionsThese findings demonstrated that ivermectin significantly enhanced the anti-cancer efficacy of chemotherapeutic drugs to tumor cells, especially in the drug-resistant cells. Thus, ivermectin, a FDA-approved antiparasitic drug, could potentially be used in combination with chemotherapeutic agents to treat cancers and in particular, the drug-resistant cancers.

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Severe metabolic alterations in liver cancer lead to ERK pathway activation and drug resistance.

Publications

Severe metabolic alterations in liver cancer lead to ERK pathway activation and drug resistance.

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