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

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...

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Published in:Journal of experimental & clinical cancer research 2019-08, Vol.38 (1)
Main Authors: Pak, Sahyun, Park, Sejun, Kim, Yunlim, Park, Jung-Hyuck, Park, Chan-Hee, Lee, Kyoung-June, Kim, Choung-soo, Ahn, Hanjong
Format: Article
Language:English
Subjects:
Abiraterone
Analysis
Androgen receptors
Apoptosis
Biochemistry
Cancer cells
Cancer patients
Cell death
Cellular signal transduction
Enzalutamide
Fluorescence
Fluorescence microscopy
Genetic aspects
Luciferase
Microscopy
Novels
Prostate cancer
Treatment outcome
Tumors
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Summary: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/[beta]-catenin signaling plays an important role in CRPC, the antitumor activity and mechanism of action of CWP232291, a small molecule [beta]-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/[beta]-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 [beta]-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 [beta]-catenin inhibitor CWP232291 in CRPC, our results show that inducing ER stress and targeting WNT/[beta]-catenin signaling may be a novel strategy against CRPC. Keywords: Prostate cancer, Castration-resistant, WNT signaling pathway, Endoplasmic reticulum stress
ISSN:0392-9078
DOI:10.1186/s13046-019-1342-5