Pristimerin induces apoptosis and autophagy via activation of ROS/ASK1/JNK pathway in human breast cancer in vitro and in vivo

Qun Zhao,Jing Zhong,Ziting Ren,Junjun Jia,Xiang Li,Yingxiang Liu,Yun Bi,Yongqiang Liu,Xianjun Yu,Mengting Yu

doi:10.1038/s41420-019-0208-0

Abstract

Breast cancer is the most common malignant tumor in women, and progress toward long-term survival has stagnated. Pristimerin, a natural quinonemethide triterpenoid, exhibits potential anti-tumor effects on various cancers. However, the underlying mechanism remains poorly understood. In this study, we found that pristimerin reduced the viability of breast cancer cells in vitro and the growth of xenografts in vivo, and these reductions were accompanied by thioredoxin-1 (Trx-1) inhibition and ASK1 and JNK activation. The results showed that pristimerin inhibited cell cycle progression and triggered cell apoptosis and autophagy. Furthermore, we found that the generation of reactive oxygen species (ROS) was a critical mediator in pristimerin-induced cell death. Enhanced ROS generation by pristimerin activated the ASK1/JNK signaling pathway. Inhibition of ROS with N-acetyl cysteine (NAC) significantly decreased pristimerin-induced cell death by inhibiting the phosphorylation of ASK1 and JNK. Taken together, these results suggest a critical role for the ROS/ASK1/JNK pathway in the anticancer activity of pristimerin.

Highlights

Breast cancer is a leading cause of cancer deaths in women worldwide[1,2]
Western blot analysis revealed that SP600125 and N-acetyl cysteine (NAC) reversed pristimerin-induced activation of apoptosis-related proteins (Fig. 5c). Both SP600125 and NAC significantly blocked the levels of LC3-II, p62 and Beclin-1 expression (Fig. 5d). These results reveal that cell apoptosis and autophagy provoked by pristimerin are associated with JNK activation and Reactive oxygen species (ROS) generation
Overproduction of ROS induced by pristimerin resulted in apoptosis signal-regulating kinase 1 (ASK1)/JNK activation, which caused cell apoptosis and autophagy (Fig. 8)

Summary

Introduction

Breast cancer is a leading cause of cancer deaths in women worldwide[1,2]. It accounts for 30% of all new cancer diagnoses and 14% of all cancer deaths in women[2]. The 5-year survival rate for breast cancer patients has improved due to surgery, chemotherapy and radiotherapy, severe side effects and drug resistance have become major challenges in clinical practice[3]. The identification of novel drugs for the treatment of breast cancer is urgently needed. ROS are in balance with biochemical antioxidants. Accumulating evidence has suggested that chemotherapeutic agents induce cell death by enhancing ROS generation[8,9]

Methods

Results

Conclusion