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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2019

Open Access 01-12-2019 | Prostate Cancer | Research

The small molecule WNT/β-catenin inhibitor CWP232291 blocks the growth of castration-resistant prostate cancer by activating the endoplasmic reticulum stress pathway

Authors: Sahyun Pak, Sejun Park, Yunlim Kim, Jung-Hyuck Park, Chan-Hee Park, Kyoung-June Lee, Choung-soo Kim, Hanjong Ahn

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2019

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Abstract

Background

Androgen receptor (AR)-targeted treatments improve the survival of castration-resistant prostate cancer (CRPC) patients; however, secondary resistance to these agents ultimately occurs in virtually all patients. Therefore, alternative therapeutic targets are urgently needed. Since growing evidence demonstrates that WNT/β-catenin signaling plays an important role in CRPC, the antitumor activity and mechanism of action of CWP232291, a small molecule β-catenin inhibitor, were investigated in prostate cancer.

Methods

We assessed the antitumor activity of CWP232291 in prostate cancer cell lines and primary cells derived from CRPC patients. The effect of CWP232291 on apoptotic cell death, endoplasmic reticulum (ER) stress, cell viability, and WNT/β-catenin signaling was evaluated by flow cytometry, western blotting, luciferase reporter assay, and fluorescence microscopy. Antitumor efficacy was assessed in two CRPC xenograft mouse models.

Results

CWP232291 induced ER stress, resulting in upregulation of the proapoptotic protein CHOP and activation of caspase-3-dependent apoptosis. In addition, CWP232291 suppressed the expression of β-catenin by affecting WNT-dependent transcriptional activity, and downregulated AR and its splice variants in prostate cancer cells. Antitumor activity was observed in prostate cancer cells in vitro and ex vivo, and antitumor efficacy was observed in vivo.

Conclusions

Beyond providing preclinical evidence of therapeutic efficacy for the novel small molecule β-catenin inhibitor CWP232291 in CRPC, our results show that inducing ER stress and targeting WNT/β-catenin signaling may be a novel strategy against CRPC.
Appendix
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Metadata
Title
The small molecule WNT/β-catenin inhibitor CWP232291 blocks the growth of castration-resistant prostate cancer by activating the endoplasmic reticulum stress pathway
Authors
Sahyun Pak
Sejun Park
Yunlim Kim
Jung-Hyuck Park
Chan-Hee Park
Kyoung-June Lee
Choung-soo Kim
Hanjong Ahn
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2019
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-019-1342-5

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