title: PRK1/PKN1 controls migration and metastasis of androgen-independent prostate cancer cells.
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. 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.
authors.affiliation: Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg 79106, Germany.
authors.forename: Cordula A
authors.initials: CA
authors.lastname: Jilg
authors.affiliation: Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg 79106, Germany. University of Freiburg, Faculty of Biology, Freiburg 79104, Germany.
authors.forename: Anett
authors.initials: A
authors.lastname: Ketscher
authors.affiliation: Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg 79106, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Metzger
authors.affiliation: Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg 79106, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Hummel
authors.affiliation: Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg 79106, Germany.
authors.forename: Dominica
authors.initials: D
authors.lastname: Willmann
authors.affiliation: Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg 79106, Germany. Universitätsklinikum Köln, Institut für Pathologie, Köln 50937, Germany.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Rüsseler
authors.affiliation: Department of Pathology, University Medical Center, Freiburg, Germany.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Drendel
authors.affiliation: Adolf-Butenandt Institute and Munich Center of Integrated Protein Science (CIPS), Ludwig-Maximilians-University of Munich, Munich 80336, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Imhof
authors.affiliation: Institute of Pharmaceutical Sciences, University of Freiburg, Freiburg 79104, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Jung
authors.affiliation: Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg 79106, Germany.
authors.forename: Henriette
authors.initials: H
authors.lastname: Franz
authors.affiliation: Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg 79106, Germany. University of Freiburg, Faculty of Biology, Freiburg 79104, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hölz
authors.affiliation: Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg 79106, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Krönig
authors.affiliation: Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg 79106, Germany.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Müller
authors.affiliation: Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg 79106, Germany. BIOSS Centre of Biological Signalling Studies, Albert-Ludwigs-University, Freiburg, Germany. Deutsches Konsortium für Translationale Krebsforschung (DKTK), Standort Freiburg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Schüle
mesh_terms: D000728:Androgens / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome; D014162:Transfection
chemical_list: D000728:Androgens; C061570:protein kinase N; D011493:Protein Kinase C