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

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...

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Main Authors:	Shao, Fang-Yuan, Wang, Sheng, Li, Hong-Yu, Chen, Wen-Bo, Wang, Guo-Cai, Ma, Dong-Lei, Wong, Nai Sum, Xiao, Hao, Liu, Qiu-Ying, Zhou, Guang-Xiong, Li, Yao-Lan, Li, Man-Mei, Wang, Yi-Fei, Liu, Zhong
Format:	Online
Language:	English
Published:	Impact Journals LLC 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872749/

id	pubmed-4872749
recordtype	oai_dc
spelling	pubmed-48727492016-05-25 EM23, a natural sesquiterpene lactone, targets thioredoxin reductase to activate JNK and cell death pathways in human cervical cancer cells Shao, Fang-Yuan Wang, Sheng Li, Hong-Yu Chen, Wen-Bo Wang, Guo-Cai Ma, Dong-Lei Wong, Nai Sum Xiao, Hao Liu, Qiu-Ying Zhou, Guang-Xiong Li, Yao-Lan Li, Man-Mei Wang, Yi-Fei Liu, Zhong Research Paper 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. Impact Journals LLC 2016-01-07 /pmc/articles/PMC4872749/ /pubmed/26758418 http://dx.doi.org/10.18632/oncotarget.6828 Text en Copyright: © 2016 Shao et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Shao, Fang-Yuan Wang, Sheng Li, Hong-Yu Chen, Wen-Bo Wang, Guo-Cai Ma, Dong-Lei Wong, Nai Sum Xiao, Hao Liu, Qiu-Ying Zhou, Guang-Xiong Li, Yao-Lan Li, Man-Mei Wang, Yi-Fei Liu, Zhong
spellingShingle	Shao, Fang-Yuan Wang, Sheng Li, Hong-Yu Chen, Wen-Bo Wang, Guo-Cai Ma, Dong-Lei Wong, Nai Sum Xiao, Hao Liu, Qiu-Ying Zhou, Guang-Xiong Li, Yao-Lan Li, Man-Mei Wang, Yi-Fei Liu, Zhong EM23, a natural sesquiterpene lactone, targets thioredoxin reductase to activate JNK and cell death pathways in human cervical cancer cells
author_facet	Shao, Fang-Yuan Wang, Sheng Li, Hong-Yu Chen, Wen-Bo Wang, Guo-Cai Ma, Dong-Lei Wong, Nai Sum Xiao, Hao Liu, Qiu-Ying Zhou, Guang-Xiong Li, Yao-Lan Li, Man-Mei Wang, Yi-Fei Liu, Zhong
author_sort	Shao, Fang-Yuan
title	EM23, a natural sesquiterpene lactone, targets thioredoxin reductase to activate JNK and cell death pathways in human cervical cancer cells
title_short	EM23, a natural sesquiterpene lactone, targets thioredoxin reductase to activate JNK and cell death pathways in human cervical cancer cells
title_full	EM23, a natural sesquiterpene lactone, targets thioredoxin reductase to activate JNK and cell death pathways in human cervical cancer cells
title_fullStr	EM23, a natural sesquiterpene lactone, targets thioredoxin reductase to activate JNK and cell death pathways in human cervical cancer cells
title_full_unstemmed	EM23, a natural sesquiterpene lactone, targets thioredoxin reductase to activate JNK and cell death pathways in human cervical cancer cells
title_sort	em23, a natural sesquiterpene lactone, targets thioredoxin reductase to activate jnk and cell death pathways in human cervical cancer cells
description	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.
publisher	Impact Journals LLC
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872749/
_version_	1613581465570770944

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

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