Alantolactone promotes ER stress-mediated apoptosis by inhibition of TrxR1 in triple-negative breast cancer cell lines and in a mouse model.

Changtian Yin,Peng Zou,Qiulin Zhou,Vinothkumar Rajamanickam,Wangyu Zhu,Ouchen Wang,Xiangjie Huang,Xi Chen,Ri Cui,Guang Liang,Xuanxuan Dai,Canwei Wang,Xiaohua Zhang,Chengguang Zhao

doi:10.1111/jcmm.14139

Abstract

Triple‐negative breast cancer (TNBC) is a subtype of breast cancer with poor clinical outcome and currently no effective targeted therapies are available. Alantolactone (ATL), a sesquiterpene lactone, has been shown to have potential anti‐tumour activity against various cancer cells. However, the underlying mechanism and therapeutic effect of ATL in the TNBC are largely unknown. In the present study, we found that ATL suppresses TNBC cell viability by reactive oxygen species (ROS) accumulation and subsequent ROS‐dependent endoplasmic reticulum (ER) stress both in vitro and in vivo. Thioredoxin reductase 1 (TrxR1) expression and activity of were significantly up‐regulated in the TNBC tissue specimens compare to the normal adjacent tissues. Further analyses showed that ATL inhibits the activity of TrxR1 both in vitro and in vivo in TNBC and knockdown of TrxR1 in TNBC cells sensitized ATL‐induced cell apoptosis and ROS increase. These results will provide pre‐clinical evidences that ATL could be a potential therapeutic agent against TNBC by promoting ROS‐ER stress‐mediated apoptosis through partly targeting TrxR1.

Highlights

Breast cancer is undoubtedly one of the most common malignancies and is the second leading cause of cancer‐related death for Changtian Yin and Xuanxuan Dai have contributed to this work.women worldwide.[1]
Our results showed that Triple‐negative breast cancer (TNBC) specimens displayed significantly increased Thioredoxin reductase 1 (TrxR1) immunoreactivity compared with the normal adjacent breast tissue from the same patient
We found that ATL effectively induces apoptosis and inhibits proliferation in TNBC cells through reactive oxygen species (ROS)‐dependent endoplasmic reticulum (ER)‐stress pathway by decreasing TrxR1 activity

Summary

| INTRODUCTION

Breast cancer is undoubtedly one of the most common malignancies and is the second leading cause of cancer‐related death for Changtian Yin and Xuanxuan Dai have contributed to this work. Thioredoxin (Trx)/thioredoxin reductase (TrxR) system has been reported to involve in oxidative stress‐induced apoptosis in cancer cells.[18,19] Increased thioredoxin levels contribute to the cancer cell growth and resistance to chemotherapy.[19] Various anti‐cancer drugs have been reported to directly or indirectly inhibit TrxR to reverse malignant characteristics.[20] Thioredoxin reductase 1 (TrxR1) is a major redox regulator in mammalian cells and has been reported to be overexpressed in many cancer cells, such as cervical, hepatoma, pancreatic, gastric, lung and breast cancers.[21,22,23,24,25,26] TrxR1 has emerged as a promising biomarker and drugable target for cancer therapy This raises the questions whether TrxR1 is overexpressed in TNBC, and whether ATL targets TrxR system to generate ROS.

| RESULTS

Findings

| DISCUSSION