Research Papers:

MED15 overexpression in prostate cancer arises during androgen deprivation therapy via PI3K/mTOR signaling

Anne Offermann, Ignacija Vlasic, Isabella Syring, Wenzel Vogel, Christian Ruiz, Tobias Zellweger, Cyrill A. Rentsch, Susanne Hagedorn, Jochen Behrends, Michael Nowak, Axel Merseburger, Lukas Bubendorf, Jutta Kirfel, Stefan Duensing, David Adler and Sven Perner _

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Oncotarget. 2017; 8:7964-7976. https://doi.org/10.18632/oncotarget.13860

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Anne Offermann1,*, Ignacija Vlasic1,*, Isabella Syring2,6,7, Wenzel Vogel1, Christian Ruiz3, Tobias Zellweger4, Cyrill A. Rentsch5, Susanne Hagedorn1, Jochen Behrends8, Michael Nowak6,7, Axel Merseburger9, Lukas Bubendorf3, Jutta Kirfel7, Stefan Duensing10, David Adler1,*, Sven Perner1,*

1Pathology of the University Medical Center Schleswig-Holstein, Campus Luebeck and Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany

2Department of Urology, University Hospital Bonn, Bonn, Germany

3Institute for Pathology, University Hospital Basel, Basel, Switzerland

4Department of Urology, St. Claraspital, Basel, Switzerland

5Department of Urology, University Hospital Basel, Basel, Switzerland

6Section of Prostate Cancer Research, Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, Bonn, Germany

7Institute of Pathology, Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, Bonn, Germany

8Core Facility Fluorescence Cytometry, Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany

9Department of Urology, University Hospital Luebeck, Luebeck, Germany

10Section of Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Heidelberg, Germany

*These authors have contributed equally

to this work

Correspondence to:

Sven Perner, email: sven.perner@uksh.de

Keywords: mediator complex, MED15, castration-resistant prostate cancer, androgen deprivation, PI3 kinase

Received: April 15, 2016    Accepted: November 21, 2016    Published: December 10, 2016


Androgen deprivation therapy (ADT) is the main therapeutic option for advanced prostate cancer (PCa). After initial regression, most tumors develop into castration-resistant PCa (CRPC). Previously, we found the Mediator complex subunit MED15 to be overexpressed in CRPC and to correlate with clinical outcome. Therefore, we investigated whether MED15 is implicated in the signaling changes taking place during progression to CRPC. Immunohistochemistry (IHC) for MED15 on matched samples from the same patients before and after ADT reveals significantly increased MED15 expression after ADT in 72%. A validation cohort comprising samples before and after therapy confirmed our observations. Protein analysis for pAKT and pSMAD3 shows that MED15 correlates with PI3K and TGFß activities, respectively, and that hyper-activation of both pathways simultaneously correlates with highest levels of MED15. We further show that MED15 protein expression increases in LNCaP cells under androgen deprivation, and via EGF mediated PI3K activation. PI3K/mTOR and TGFß-receptor inhibition results in decreased MED15 expression. MED15 knockdown reduces LNCaP cell viability and induces apoptosis during androgen deprivation, while cell cycle is not affected. Collectively, MED15 overexpression arises during ADT via hyper-activation of PI3K/mTOR signaling, thus MED15 may serve as a predictive marker for response to PI3K/mTOR inhibitors. Furthermore, MED15 is potentially a therapeutic target for the treatment of CRPC.

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