Canine REIC/Dkk-3 interacts with SGTA and restores androgen receptor signalling in androgen-independent prostate cancer cell lines

Yuiko Kato,Daigo Azakami,Nobuhiro Nakao,Masami Watanabe,Masami Morimatsu,Masaki Michishita,Makoto Bonkobara,Toshinori Omi,Kazuhiko Ochiai,Shota Kawakami

doi:10.1186/s12917-017-1094-4

Abstract

BackgroundThe pathological condition of canine prostate cancer resembles that of human androgen-independent prostate cancer. Both canine and human androgen receptor (AR) signalling are inhibited by overexpression of the dimerized co-chaperone small glutamine-rich tetratricopeptide repeat-containing protein α (SGTA), which is considered to cause the development of androgen-independency. Reduced expression in immortalised cells (REIC/Dkk-3) interferes with SGTA dimerization and rescues AR signalling. This study aimed to assess the effects of REIC/Dkk-3 and SGTA interactions on AR signalling in the canine androgen-independent prostate cancer cell line CHP-1.ResultsMammalian two-hybrid and Halo-tagged pull-down assays showed that canine REIC/Dkk-3 interacted with SGTA and interfered with SGTA dimerization. Additionally, reporter assays revealed that canine REIC/Dkk-3 restored AR signalling in both human and canine androgen-independent prostate cancer cells. Therefore, we confirmed the interaction between canine SGTA and REIC/Dkk-3, as well as their role in AR signalling.ConclusionsOur results suggest that this interaction might contribute to the development of a novel strategy for androgen-independent prostate cancer treatment. Moreover, we established the canine androgen-independent prostate cancer model as a suitable animal model for the study of this type of treatment-refractory human cancer.

Highlights

The pathological condition of canine prostate cancer resembles that of human androgenindependent prostate cancer
We analysed the interaction between canine respond to androgenReduced expression in immortalised cells (REIC)/Dkk-3 and small glutamine-rich tetratricopeptide repeat-containing protein α (SGTA) by an Mammalian two-hybrid (MTH) assay in 293 T cells using cotransfection and expression of each protein cloned into GAL4-DBD and VP16-AD plasmids, respectively
Here, we demonstrated that the canine tumour suppressor REIC/Dkk-3 interacts with SGTA, which is a cochaperone known to interact with Hsp70/Hsp90 and the cytosolic immature androgen receptor (AR) complex [3, 17, 19, 26]

Summary

Introduction

The pathological condition of canine prostate cancer resembles that of human androgenindependent prostate cancer. Both canine and human androgen receptor (AR) signalling are inhibited by overexpression of the dimerized co-chaperone small glutamine-rich tetratricopeptide repeat-containing protein α (SGTA), which is considered to cause the development of androgen-independency. Reduced expression in immortalised cells (REIC/Dkk-3) interferes with SGTA dimerization and rescues AR signalling. This study aimed to assess the effects of REIC/Dkk-3 and SGTA interactions on AR signalling in the canine androgen-independent prostate cancer cell line CHP-1. Kato et al BMC Veterinary Research (2017) 13:170 in normal cells, whereas its expression is significantly downregulated in various cancer cell types, including human and canine prostate cancer [7]. Previous studies showed that overexpression of REIC/Dkk-3 using adenoviral or plasmid vectors induces apoptosis in various cancer cell lines, but not in normal cells, via c-Jun-NH2-terminal kinase (JNK) and cJun activation, and endoplasmic reticulum (ER) stress signalling [7, 10–13]

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