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.
Highlights
Prostate cancer (PCa) is the second leading cause of cancer deaths in men worldwide [1]
We describe a novel mechanism controlling the metastatic behavior of PCa cells and identify PRK1 as a promising target to prevent metastasis of androgen-independent PCa
To investigate the role of PRK1 during metastatic processes of PCa we first analyzed whether modulation of PRK1 levels in androgen-independent prostate tumor cell lines such as PC-3M-luc2 and Du145 influences migration and invasion
Summary
Prostate cancer (PCa) is the second leading cause of cancer deaths in men worldwide [1]. Due to the hormone-dependent properties of PCa, the majority of men with relapsing PCa initially responds to hormonal depletion but will inevitably develop www.impactjournals.com/oncotarget androgen-independent PCa over time, followed by first regional and later distant metastases. For this stage of disease there is no curative therapy available. The most common cause of clinical complications and subsequent death originates from metastases. This clinical dilemma urgently calls for new therapeutic strategies to treat advanced PCa
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