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Oncogene. 2019 Jun;38(23):4496-4511. doi: 10.1038/s41388-019-0732-7. Epub 2019 Feb 11.

Protein Kinase N1 control of androgen-responsive serum response factor action provides rationale for novel prostate cancer treatment strategy.

Author information

1
Department of Cancer Biology, Cleveland Clinic, Cleveland, OH, USA.
2
Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, OH, USA.
3
Department of Cancer Genetics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
4
Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
5
Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
6
Department of Pathology and Laboratory Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
7
Department of Anatomic Pathology, Cleveland Clinic, Cleveland, OH, USA.
8
Department of Urology, University of California, San Diego, LaJolla, CA, USA.
9
Masonic Cancer Center and Departments of Laboratory Medicine and Pathology and Urology, University of Minnesota, Minneapolis, MN, USA.
10
Department of Urology, Cleveland Clinic, Cleveland, OH, USA.
11
Department of Hematology/Medical Oncology, Cleveland Clinic, Cleveland, OH, USA.
12
Department of Cancer Biology, Cleveland Clinic, Cleveland, OH, USA. heemerh@ccf.org.
13
Department of Urology, Cleveland Clinic, Cleveland, OH, USA. heemerh@ccf.org.
14
Department of Hematology/Medical Oncology, Cleveland Clinic, Cleveland, OH, USA. heemerh@ccf.org.

Abstract

Sustained reliance on androgen receptor (AR) after failure of AR-targeting androgen deprivation therapy (ADT) prevents effective treatment of castration-recurrent (CR) prostate cancer (CaP). Interfering with the molecular machinery by which AR drives CaP progression may be an alternative therapeutic strategy but its feasibility remains to be tested. Here, we explore targeting the mechanism by which AR, via RhoA, conveys androgen-responsiveness to serum response factor (SRF), which controls aggressive CaP behavior and is maintained in CR-CaP. Following a siRNA screen and candidate gene approach, RNA-Seq studies confirmed that the RhoA effector Protein Kinase N1 (PKN1) transduces androgen-responsiveness to SRF. Androgen treatment induced SRF-PKN1 interaction, and PKN1 knockdown or overexpression severely impaired or stimulated, respectively, androgen regulation of SRF target genes. PKN1 overexpression occurred during clinical CR-CaP progression, and hastened CaP growth and shortened CR-CaP survival in orthotopic CaP xenografts. PKN1's effects on SRF relied on its kinase domain. The multikinase inhibitor lestaurtinib inhibited PKN1 action and preferentially affected androgen regulation of SRF over direct AR target genes. In a CR-CaP patient-derived xenograft, expression of SRF target genes was maintained while AR target gene expression declined and proliferative gene expression increased. PKN1 inhibition decreased viability of CaP cells before and after ADT. In patient-derived CaP explants, lestaurtinib increased AR target gene expression but did not significantly alter SRF target gene or proliferative gene expression. These results provide proof-of-principle for selective forms of ADT that preferentially target different fractions of AR's transcriptional output to inhibit CaP growth.

PMID:
30742064
PMCID:
PMC6771259
DOI:
10.1038/s41388-019-0732-7
[Indexed for MEDLINE]
Free PMC Article

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