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

^*Correspondence: houtao1994@126.com (Tao Hou); zengjin1984@126.com (Jin Zeng)
^†These authors contributed equally.
Academic Editor: Alfonso Urbanucci

Front. Biosci. (Landmark Ed) 2022, 27(12), 335; https://doi.org/10.31083/j.fbl2712335

Submitted: 29 August 2022 | Revised: 25 October 2022 | Accepted: 22 November 2022 | Published: 28 December 2022

This is an open access article under the CC BY 4.0 license.

Abstract

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.

Keywords

β-ionone

prostate cancer

epithelial-mesenchymal transition

Wnt/β-catenin pathway

ubiquitination

Funding

82073304/National Natural Science Foundation of China

Figures

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Fig. 1.

$\beta$ -Ionone inhibits migration and invasion of prostate cancer cells. (A) MTT assays were performed to determine the cell viabilities of PC3, 22RV1 and BPH-1 treated with different concentrations of $\beta$ -ionone for 24 and 48 h. (B) EdU staining explore the Edu-positive rate of cells after 24 h of $\beta$ -ionone treatment. (C) Wound healing assays were performed on PC3, 22RV1 and BPH-1 cells treated with DMSO or 180 $\mu$ M of $\beta$ -ionone. (D) Transwell migration and (E) invasion assays were used to investigate the migration and invasion abilities of PC3 and 22RV1 cells after treatment with DMSO or 180 $\mu$ M $\beta$ -ionone. Magnification, $\times{}$ 100. Scale bar, 20 $\mu$ m. *p $<$ 0.05, **p $<$ 0.01, ***p $<$ 0.001 and ****p $<$ 0.0001.

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