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

TitleEM23, a natural sesquiterpene lactone, targets thioredoxin reductase to activate JNK and cell death pathways in human cervical cancer cells
Authors
Issue Date2016
PublisherImpact Journals LLC. The Journal's web site is located at http://www.impactjournals.com/oncotarget/index.html
Citation
Oncotarget, 2016, v. 7 n. 6, p. 6790-6808 How to Cite?
AbstractSesquiterpene 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.
Persistent Identifierhttp://hdl.handle.net/10722/236404
ISSN
2015 Impact Factor: 5.008
2015 SCImago Journal Rankings: 2.294
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorShao, FY-
dc.contributor.authorWang, S-
dc.contributor.authorLi, HY-
dc.contributor.authorChen, WB-
dc.contributor.authorWang, GC-
dc.contributor.authorMa, DL-
dc.contributor.authorWong, NS-
dc.contributor.authorXiao, H-
dc.contributor.authorLiu, QY-
dc.contributor.authorZhou, GX-
dc.contributor.authorLi, YL-
dc.contributor.authorLi, MM-
dc.contributor.authorWang, YF-
dc.contributor.authorLiu, Z-
dc.date.accessioned2016-11-25T00:52:54Z-
dc.date.available2016-11-25T00:52:54Z-
dc.date.issued2016-
dc.identifier.citationOncotarget, 2016, v. 7 n. 6, p. 6790-6808-
dc.identifier.issn1949-2553-
dc.identifier.urihttp://hdl.handle.net/10722/236404-
dc.description.abstractSesquiterpene 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.-
dc.languageeng-
dc.publisherImpact Journals LLC. The Journal's web site is located at http://www.impactjournals.com/oncotarget/index.html-
dc.relation.ispartofOncotarget-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleEM23, a natural sesquiterpene lactone, targets thioredoxin reductase to activate JNK and cell death pathways in human cervical cancer cells-
dc.typeArticle-
dc.identifier.emailWong, NS: nswong@hkucc.hku.hk-
dc.identifier.authorityWong, NS=rp00340-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.18632/oncotarget.6828-
dc.identifier.pmcidPMC4872749-
dc.identifier.hkuros268879-
dc.identifier.volume7-
dc.identifier.issue6-
dc.identifier.spage6790-
dc.identifier.epage6808-
dc.identifier.isiWOS:000376123100031-
dc.publisher.placeUnited States-

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