Oncotarget

Research Papers:

Eukaryotic elongation factor 2 is a prognostic marker and its kinase a potential therapeutic target in HCC

Leona L. Pott, Sascha Hagemann, Henning Reis, Kristina Lorenz, Thilo Bracht, Thomas Herold, Boris V. Skryabin, Dominik A. Megger, Julia Kälsch, Frank Weber, Barbara Sitek and Hideo A. Baba _

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Oncotarget. 2017; 8:11950-11962. https://doi.org/10.18632/oncotarget.14447

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Abstract

Leona L. Pott1,2, Sascha Hagemann1, Henning Reis1, Kristina Lorenz3,4,5, Thilo Bracht2, Thomas Herold1, Boris V. Skryabin6, Dominik A. Megger2, Julia Kälsch1,7, Frank Weber8, Barbara Sitek2, Hideo A. Baba1

1Institute of Pathology, University of Duisburg-Essen, Essen, Germany

2Medizinisches Proteom-Center, Ruhr-University Bochum, Bochum, Germany

3Institute of Pharmacology, University of Wuerzburg, Wuerzburg, Germany

4Leibniz-Institut für Analytische Wissenschaften –ISAS-e.V., Dortmund, Germany

5West German Heart and Vascular Center, University of Duisburg-Essen, Essen, Germany

6Transgenic Animal and Genetic Engineering Models (TRAM), Westphalian Wilhelms University, Muenster, Germany

7Department of Gastroenterology and Hepatology, University of Duisburg-Essen, Essen, Germany

8Department of General, Visceral and Transplantation Surgery, University of Duisburg-Essen, Essen, Germany

Correspondence to:

Hideo A. Baba, email: [email protected]

Keywords: eEF2, eEF2 kinase, prognosis, hepatocellular carcinoma

Received: September 14, 2016     Accepted: December 18, 2016     Published: January 02, 2017

ABSTRACT

Hepatocellular carcinoma is a cancer with increasing incidence and largely refractory to current anticancer drugs. Since Sorafenib, a multikinase inhibitor has shown modest efficacy in advanced hepatocellular carcinoma additional treatments are highly needed. Protein phosphorylation via kinases is an important post-translational modification to regulate cell homeostasis including proliferation and apoptosis. Therefore kinases are valuable targets in cancer therapy. To this end we performed 2D differential gel electrophoresis and mass spectrometry analysis of phosphoprotein-enriched lysates of tumor and corresponding non-tumorous liver samples to detect differentially abundant phosphoproteins to screen for novel kinases as potential drug targets. We identified 34 differentially abundant proteins in phosphoprotein enriched lysates. Expression and distribution of the candidate protein eEF2 and its phosphorylated isoform was validated immunohistochemically on 78 hepatocellular carcinoma and non-tumorous tissue samples. Validation showed that total eEF2 and phosphorylated eEF2 at threonine 56 are prognostic markers for overall survival of HCC-patients. The activity of the regulating eEF2 kinase, compared between tumor and non-tumorous tissue lysates by in vitro kinase assays, is more than four times higher in tumor tissues. Functional analyzes regarding eEF2 kinase were performed in JHH5 cells with CRISPR/Cas9 mediated eEF2 kinase knock out. Proliferation and growth is decreased in eEF2 kinase knock out cells.

Conclusion: eEF2 and phosphorylated eEF2 are prognostic markers for survival of hepatocellular carcinoma patients and the regulating eEF2 kinase is a potential drug target for tumor therapy.


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