title: EM23, a natural sesquiterpene lactone, targets thioredoxin reductase to activate JNK and cell death pathways in human cervical cancer cells.
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.
authors.affiliation: 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.|Faculty of Health Sciences, University of Macau, Macau SAR, China.
authors.forename: Fang-Yuan
authors.initials: FY
authors.lastname: Shao
authors.affiliation: 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.
authors.forename: Sheng
authors.initials: S
authors.lastname: Wang
authors.affiliation: College of Pharmacy, Jinan University, Guangzhou, China.
authors.forename: Hong-Yu
authors.initials: HY
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Wen-Bo
authors.initials: WB
authors.lastname: Chen
authors.affiliation: College of Pharmacy, Jinan University, Guangzhou, China.
authors.forename: Guo-Cai
authors.initials: GC
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Dong-Lei
authors.initials: DL
authors.lastname: Ma
authors.affiliation: Department of Biochemistry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Nai Sum
authors.initials: NS
authors.lastname: Wong
authors.affiliation: University of The Chinese Academy of Sciences, Beijing, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Xiao
authors.affiliation: 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.
authors.forename: Qiu-Ying
authors.initials: QY
authors.lastname: Liu
authors.affiliation: College of Pharmacy, Jinan University, Guangzhou, China.
authors.forename: Guang-Xiong
authors.initials: GX
authors.lastname: Zhou
authors.affiliation: College of Pharmacy, Jinan University, Guangzhou, China.
authors.forename: Yao-Lan
authors.initials: YL
authors.lastname: Li
authors.affiliation: College of Pharmacy, Jinan University, Guangzhou, China.
authors.forename: Man-Mei
authors.initials: MM
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Yi-Fei
authors.initials: YF
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Liu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D007783:Lactones / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D061986:MCF-7 Cells; D017382:Reactive Oxygen Species / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014162:Transfection; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology
chemical_list: C000613545:EM23 sesquiterpene; D007783:Lactones; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; D013880:Thioredoxin-Disulfide Reductase; D048670:MAP Kinase Kinase 4
keywords: ROS; apoptosis; sesquiterpene lactone; thioredoxin; thioredoxin reductase