ss-ionone Inhibits Epithelial-Mesenchymal Transition (EMT) in Prostate Cancer Cells by Negatively Regulating the Wnt/ss-Catenin Pathway

Background: beta-ionone is a terminal cyclic analog of beta-carotenoids widely found in plants. In recent years, accumulating evidence has shown that beta-ionone exerts antitumor effects on various malignant tumors. However, limited studies have revealed the role of beta-ionone in regulating the epithelial-mesenchymal transition (EMT) of prostate cancer (PCa) cells. This study aimed to investigate the effect of beta-ionone on the EMT process of PCa, focusing on Wnt/beta-catenin signaling pathway. Methods: After exposure to beta-ionone, cell viability was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and the Brdu proliferation assay. The Transwell and wounding healing were used to investigate the migration and invasion abilities of PCa cells. Expression of proteins involved in the EMT process (E-cadherin, N-cadherin, vimentin) and proteins in the Wnt/beta-catenin pathway (beta-catenin, GSK3-beta, and p-GSK3-beta) were explored by western blotting. The effects of beta-ionone on beta-catenin degradation were explored by cycloheximide tracking assay and in vitro ubiquitination assay. Nude mouse xenograft model was served as the model system in vivo. Results: The migration, invasion, and EMT process of PCa Human PC-3 prostate adenocarcinoma cells (PC3) and Human 22RV1 prostate adenocarcinoma cells (22RV1) cells were significantly inhibited after beta-ionone treatment. In addition, beta-ionone also inhibited the growth and EMT process of subcutaneous xenograft tumors in nude mice. The study also found that beta-catenin, which promotes EMT, was downregulated after beta-ionone treatment. Further mechanistic studies revealed that beta-ionone inhibited the Wnt/beta-catenin pathway by accelerating the ubiquitination and degradation of beta-catenin in PCa, thus inhibiting the downstream migration, invasion, and EMT processes. Conclusions: These findings demonstrate that beta-ionone may be a potential natural compound targeting the Wnt/beta-catenin pathway for the treatment of PCa.