EM23, a natural sesquiterpene lactone, targets thioredoxin reductase to activate JNK and cell death pathways in human cervical cancer cells

Abstract

// Fang-Yuan Shao 1, 3, * , Sheng Wang 1, * , Hong-Yu Li 2, * , Wen-Bo Chen 1 , Guo-Cai Wang 2 , Dong-Lei Ma 1 , Nai Sum Wong 4 , Hao Xiao 5 , Qiu-Ying Liu 1 , Guang-Xiong Zhou 2 , Yao-Lan Li 2 , Man-Mei Li 2 , Yi-Fei Wang 1 , Zhong Liu 1 1 Guangzhou Jinan Biomedicine Research and Development Center, Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, China 2 College of Pharmacy, Jinan University, Guangzhou, China 3 Faculty of Health Sciences, University of Macau, Macau SAR, China 4 Department of Biochemistry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 5 University of The Chinese Academy of Sciences, Beijing, China * These authors contributed equally to this work Correspondence to: Zhong Liu, e-mail: [e-mail] Man-Mei Li, e-mail: [e-mail] Yi-Fei Wang, e-mail: [e-mail] Keywords: thioredoxin, thioredoxin reductase, sesquiterpene lactone, ROS, apoptosis Received: October 14, 2015      Accepted: December 26, 2015      Published: January 07, 2016 ABSTRACT Sesquiterpene lactones (SLs) are the active constituents of a variety of medicinal plants and found to have potential anticancer activities. However, the intracellular molecular targets of SLs and the underlying molecular mechanisms have not been well elucidated. In this study, we observed that EM23, a natural SL, exhibited anti-cancer activity in human cervical cancer cell lines by inducing apoptosis as indicated by caspase 3 activation, XIAP downregulation and mitochondrial dysfunction. Mechanistic studies indicated that EM23-induced apoptosis was mediated by reactive oxygen species (ROS) and the knockdown of thioredoxin (Trx) or thioredoxin reductase (TrxR) resulted in a reduction in apoptosis. EM23 attenuated TrxR activity by alkylation of C-terminal redox-active site Sec498 of TrxR and inhibited the expression levels of Trx/TrxR to facilitate ROS accumulation. Furthermore, inhibition of Trx/TrxR system resulted in the dissociation of ASK1 from Trx and the downstream activation of JNK. Pretreatment with ASK1/JNK inhibitors partially rescued cells from EM23-induced apoptosis. Additionally, EM23 inhibited Akt/mTOR pathway and induced autophagy, which was observed to be proapoptotic and mediated by ROS. Together, these results reveal a potential molecular mechanism for the apoptotic induction observed with SL compound EM23, and emphasize its putative role as a therapeutic agent for human cervical cancer.