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

Journal of Experimental & Clinical Cancer Research : CR
Sahyun PakHanjong Ahn

Abstract

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. 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. 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 ...Continue Reading

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Citations

Nov 14, 2019·Current Pharmaceutical Design·Morteza GhandadiSorour Ashari
Mar 19, 2020·OncoTargets and Therapy·Zhijie TanShanshan Liu
Oct 22, 2020·Pharmaceuticals·Maritza P GarridoCarmen Romero
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Jan 21, 2020·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Lei PengGuoxin Zhang
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Aug 31, 2021·Signal Transduction and Targeted Therapy·Fanyuan YuLing Ye

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Methods Mentioned

BETA
protein assay
electrophoresis
PCR
transfection
flow cytometry
xenograft
confocal microscopy
immunoprecipitation assay
xenografts
protein folding

Software Mentioned

Prism
GraphPad
GraphPad Prism®
CellQuestPro

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