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

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...

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Bibliographic Details
Published in:Oncotarget 2014-12, Vol.5 (24), p.12646-12664
Main Authors: Jilg, Cordula A, Ketscher, Anett, Metzger, Eric, Hummel, Barbara, Willmann, Dominica, Rüsseler, Vanessa, Drendel, Vanessa, Imhof, Axel, Jung, Manfred, Franz, Henriette, Hölz, Stefanie, Krönig, Malte, Müller, Judith M, Schüle, Roland
Format: Article
Language:English
Subjects:
Androgens - metabolism
Animals
Cell Line, Tumor
Cell Movement - genetics
Cell Movement - physiology
Cell Proliferation - genetics
Cell Proliferation - physiology
Humans
Male
Mice
Neoplasm Metastasis
Phosphorylation
Prostatic Neoplasms - genetics
Prostatic Neoplasms - metabolism
Prostatic Neoplasms - pathology
Protein Kinase C - genetics
Protein Kinase C - metabolism
Research Paper
Transcriptome
Transfection
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Summary: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.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.2653