Isoalantolactone induces apoptosis through ROS-mediated ER stress and inhibition of STAT3 in prostate cancer cells

Wei Chen,Fangyi Zhang,Yu Yang,Ping Li,Xueting Ye,Yi Liu,Hang Huang

doi:10.1186/s13046-018-0987-9

Abstract

BackgroundProstate cancer is one of the most commonly diagnosed cancers in men worldwide. Currently available therapies for metastatic prostate cancer are only marginally effective. Therefore, new therapeutic agents are urgently needed to improve patient outcome. Isoalantolactone (IATL), an active sesquiterpene naturally present in many vegetables and medicinal plants, is known to induce cell death and apoptosis in various cancer cell lines. Nevertheless, antitumor mechanisms initiated by IATL in cancer cells have not been fully defined.MethodsCell apoptosis and cellular ROS levels were analyzed by flow cytometry. Western blot and qRT-PCR were used to analyze the protein and mRNA levels of indicated molecules, respectively. Nude mice xenograft model was used to test the effects of IATL on prostate cancer cell growth in vivo.ResultsIn this study, we found that IATL dose-dependently inhibited cancer cell growth and induced apoptosis in PC-3 and DU145 cells. Mechanistically, our data found that IATL induced reactive oxygen species (ROS) production, resulting in the activation of endoplasmic reticulum stress pathway and eventually cell apoptosis in prostate cancer cells. IATL also decreased the protein expression levels of p-STAT3 and STAT3, and the effects of IATL were reversed by pretreatment with N-acetyl-L-cysteine (NAC). In vivo, we found that IATL inhibited the growth of prostate cancer xenografts without exhibiting toxicity. Treatment of mice bearing human prostate cancer xenografts with IATL was also associated with induction of ER stress and inhibtion of STAT3.ConclusionIn summary, our results unveil a previously unrecognized mechanism underlying the biological activity of IATL, and provide a novel anti-cancer candidate for the treatment of prostate cancer.

Highlights

Prostate cancer is one of the most commonly diagnosed cancers in men worldwide
IATL inhibits cells growth and induces apoptosis in prostate cancer cells To explore the effects of IATL on the growth of prostate cancer cells, two human prostate cancer cell lines, PC-3 and DU145 cells were treated with IATL at different concentrations (0–60 μM) for 24 h
IATL treatment significantly suppressed the expression of Bcl-2, suggesting that mitochondrial pathway is involved in IATL-induced apoptosis in prostate cancer cells (Fig. 1l-m)

Summary

Introduction

Prostate cancer is one of the most commonly diagnosed cancers in men worldwide. Isoalantolactone (IATL), an active sesquiterpene naturally present in many vegetables and medicinal plants, is known to induce cell death and apoptosis in various cancer cell lines. Prostate cancer is one of the most commonly diagnosed cancers in men worldwide, with 1.1 million new cases of prostate cancer were estimated to have occurred in 2012 [1]. Androgen deprivation therapy is effective in the first few years of treatment, most patients eventually develop resistance to this therapy and progress into castration resistant prostate cancer (CRPC) [3]. Isoalantolactone (IATL), an active sesquiterpene naturally present in many vegetables and medicinal plants, was recently identified as selectively toxic to cancer cells

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