Oncotarget

Research Papers:

PRK1/PKN1 controls migration and metastasis of androgen-independent prostate cancer cells

Cordula A. Jilg _, Anett Ketscher, Eric Metzger, Barbara Hummel, Dominica Willmann, Vanessa Rüsseler, Vanessa Drendel, Axel Imhof, Manfred Jung, Henriette Franz, Stefanie Hölz, Malte Krönig, Judith M. Müller and Roland Schüle

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Oncotarget. 2014; 5:12646-12664. https://doi.org/10.18632/oncotarget.2653

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Abstract

Cordula A. Jilg1, Anett Ketscher1,2, Eric Metzger1, Barbara Hummel1, Dominica Willmann1, Vanessa Rüsseler1,3, Vanessa Drendel4, Axel Imhof5, Manfred Jung6, Henriette Franz1, Stefanie Hölz1,2, Malte Krönig1, Judith M. Müller1, Roland Schüle1,7,8

1Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg 79106, Germany

2University of Freiburg, Faculty of Biology, Freiburg 79104, Germany

3Universitätsklinikum Köln, Institut für Pathologie, Köln 50937, Germany

4Department of Pathology, University Medical Center, Freiburg, Germany

5Adolf-Butenandt Institute and Munich Center of Integrated Protein Science (CIPS), Ludwig-Maximilians-University of Munich, Munich 80336, Germany

6Institute of Pharmaceutical Sciences, University of Freiburg, Freiburg 79104, Germany

7BIOSS Centre of Biological Signalling Studies, Albert-Ludwigs-University, Freiburg, Germany

8Deutsches Konsortium für Translationale Krebsforschung (DKTK), Standort Freiburg, Germany

Correspondence to:

R. Schüle, e-mail: roland.schuele@uniklinik-freiburg.de

Received: August 06, 2014     Accepted: October 26, 2014     Published: December 10, 2014

ABSTRACT

The major threat in prostate cancer is the occurrence of metastases in androgen-independent tumor stage, for which no causative cure is available. Here we show that metastatic behavior of androgen-independent prostate tumor cells requires the protein-kinase-C-related kinase (PRK1/PKN1) in vitro and in vivo. PRK1 regulates cell migration and gene expression through its kinase activity, but does not affect cell proliferation. Transcriptome and interactome analyses uncover that PRK1 regulates expression of migration-relevant genes by interacting with the scaffold protein sperm-associated antigen 9 (SPAG9/JIP4). SPAG9 and PRK1 colocalize in human cancer tissue and are required for p38-phosphorylation and cell migration. Accordingly, depletion of either ETS domain-containing protein Elk-1 (ELK1), an effector of p38-signalling or p38 depletion hinders cell migration and changes expression of migration-relevant genes as observed upon PRK1-depletion. Importantly, a PRK1 inhibitor prevents metastases in mice, showing that the PRK1-pathway is a promising target to hamper prostate cancer metastases in vivo.

Statement of significance

Here we describe a novel mechanism controlling the metastatic behavior of PCa cells and identify PRK1 as a promising therapeutic target to treat androgen-independent metastatic prostate cancer.


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