title: The AR/NCOA1 axis regulates prostate cancer migration by involvement of PRKD1.
abstract: Due to the urgent need for new prostate cancer (PCa) therapies, the role of androgen receptor (AR)-interacting proteins should be investigated. In this study we aimed to address whether the AR coactivator nuclear receptor coactivator 1 (NCOA1) is involved in PCa progression. Therefore, we tested the effect of long-term NCOA1 knockdown on processes relevant to metastasis formation. [(3)H]-thymidine incorporation assays revealed a reduced proliferation rate in AR-positive MDA PCa 2b and LNCaP cells upon knockdown of NCOA1, whereas AR-negative PC3 cells were not affected. Furthermore, Boyden chamber assays showed a strong decrease in migration and invasion upon NCOA1 knockdown, independently of the cell line's AR status. In order to understand the mechanistic reasons for these changes, transcriptome analysis using cDNA microarrays was performed. Protein kinase D1 (PRKD1) was found to be prominently up-regulated by NCOA1 knockdown in MDA PCa 2b, but not in PC3 cells. Inhibition of PRKD1 reverted the reduced migratory potential caused by NCOA1 knockdown. Furthermore, PRKD1 was negatively regulated by AR. Immunohistochemical staining of PCa patient samples revealed a strong increase in NCOA1 expression in primary tumors compared with normal prostate tissue, while no final conclusion could be drawn for PRKD1 expression in tumor specimens. Thus, our findings directly associate the AR/NCOA1 complex with PRKD1 regulation and cellular migration and support the concept of therapeutic inhibition of NCOA1 in PCa.
authors.affiliation: Division of Experimental UrologyDepartment of Urology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Birgit
authors.initials: B
authors.lastname: Luef
authors.affiliation: Division of Experimental UrologyDepartment of Urology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Handle
authors.affiliation: Department of Clinical and Molecular Pathology and Institute of Molecular and Translational MedicineFaculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
authors.forename: Gvantsa
authors.initials: G
authors.lastname: Kharaishvili
authors.affiliation: Department of PathologyParacelsus Medical University, Salzburg, Austria.
authors.forename: Martina
authors.initials: M
authors.lastname: Hager
authors.affiliation: Division of Molecular PathophysiologyBiocenter, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Rainer
authors.affiliation: Department of UrologyParacelsus Medical University, Salzburg, Austria.
authors.forename: Günter
authors.initials: G
authors.lastname: Janetschek
authors.affiliation: Department of UrologyParacelsus Medical University, Salzburg, Austria.
authors.forename: Stephan
authors.initials: S
authors.lastname: Hruby
authors.affiliation: Department of UrologyParacelsus Medical University, Salzburg, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Englberger
authors.affiliation: Department of Clinical and Molecular Pathology and Institute of Molecular and Translational MedicineFaculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Bouchal
authors.affiliation: Division of Experimental UrologyDepartment of Urology, Medical University of Innsbruck, Innsbruck, Austria zoran.culig@i-med.ac.at frederic.santer@i-med.ac.at.
authors.forename: Frédéric R
authors.initials: FR
authors.lastname: Santer
authors.affiliation: Division of Experimental UrologyDepartment of Urology, Medical University of Innsbruck, Innsbruck, Austria zoran.culig@i-med.ac.at frederic.santer@i-med.ac.at.
authors.forename: Zoran
authors.initials: Z
authors.lastname: Culig
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness; D056920:Nuclear Receptor Coactivator 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*
chemical_list: C410798:AR protein, human; D011944:Receptors, Androgen; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1; C089212:protein kinase D; D011493:Protein Kinase C
keywords: NCOA1; PRKD1; antiandrogen; coactivator; motility; prostate cancer