EM23, a natural sesquiterpene lactone, targets thioredoxin reductase to activate JNK and cell death pathways in human cervical cancer cells
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Fang-Yuan Shao1,3,*, Sheng Wang1,*, Hong-Yu Li2,*, Wen-Bo Chen1, Guo-Cai Wang2, Dong-Lei Ma1, Nai Sum Wong4, Hao Xiao5, Qiu-Ying Liu1, Guang-Xiong Zhou2, Yao-Lan Li2, Man-Mei Li2, Yi-Fei Wang1, Zhong Liu1
1Guangzhou Jinan Biomedicine Research and Development Center, Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, China
2College of Pharmacy, Jinan University, Guangzhou, China
3Faculty of Health Sciences, University of Macau, Macau SAR, China
4Department of Biochemistry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
5University of The Chinese Academy of Sciences, Beijing, China
*These authors contributed equally to this work
Zhong Liu, e-mail: [email protected]
Man-Mei Li, e-mail: [email protected]
Yi-Fei Wang, e-mail: [email protected]
Keywords: thioredoxin, thioredoxin reductase, sesquiterpene lactone, ROS, apoptosis
Received: October 14, 2015 Accepted: December 26, 2015 Published: January 07, 2016
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.
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