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Article: B5, a thioredoxin reductase inhibitor, induces apoptosis in human cervical cancer cells by suppressing the thioredoxin system, disrupting mitochondrion-dependent pathways and triggering autophagy

TitleB5, a thioredoxin reductase inhibitor, induces apoptosis in human cervical cancer cells by suppressing the thioredoxin system, disrupting mitochondrion-dependent pathways and triggering autophagy
Authors
KeywordsApoptosis
Cervical cancer
Curcumin analog
Thioredoxin reductase
Issue Date2015
PublisherImpact Journals LLC. The Journal's web site is located at http://www.impactjournals.com/oncotarget/index.html
Citation
Oncotarget, 2015, v. 6 n. 31, p. 30939-30956 How to Cite?
AbstractThe synthetic curcumin analog B5 is a potent inhibitor of thioredoxin reductase (TrxR) that has potential anticancer effects. The molecular mechanism underlying B5 as an anticancer agent is not yet fully understood. In this study, we report that B5 induces apoptosis in two human cervical cancer cell lines, CaSki and SiHa, as evidenced by the downregulation of XIAP, activation of caspases and cleavage of PARP. The involvement of the mitochondrial pathway in B5-induced apoptosis was suggested by the dissipation of mitochondrial membrane potential and increased expression of pro-apoptotic Bcl-2 family proteins. In B5-treated cells, TrxR activity was markedly inhibited with concomitant accumulation of oxidized thioredoxin, increased formation of reactive oxygen species (ROS), and activation of ASK1 and its downstream regulatory target p38/JNK. B5-induced apoptosis was significantly inhibited in the presence of N-acetyl-l-cysteine. Microscopic examination of B5-treated cells revealed increased presence of cytoplasmic vacuoles. The ability of B5 to activate autophagy in cells was subsequently confirmed by cell staining with acridine orange, accumulation of LC3-II, and measurement of autophagic flux. Unlike B5-induced apoptosis, autophagy induced by B5 is not ROS-mediated but a role for the AKT and AMPK signaling pathways is implied. In SiHa cells but not CaSki cells, B5-induced apoptosis was promoted by autophagy. These data suggest that the anticarcinogenic effects of B5 is mediated by complex interplay between cellular mechanisms governing redox homeostasis, apoptosis and autophagy.
Persistent Identifierhttp://hdl.handle.net/10722/218681
ISSN
2015 Impact Factor: 5.008
2015 SCImago Journal Rankings: 2.294
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorShao, FY-
dc.contributor.authorDu, ZY-
dc.contributor.authorMa, DL-
dc.contributor.authorChen, WB-
dc.contributor.authorZhang, JX-
dc.contributor.authorWang, S-
dc.contributor.authorXiao, H-
dc.contributor.authorLi, MM-
dc.contributor.authorWong, NS-
dc.contributor.authorLiu, X-
dc.contributor.authorLiu, QY-
dc.contributor.authorZhao, XD-
dc.contributor.authorYan, HZ-
dc.contributor.authorWang, YF-
dc.contributor.authorChen, CY-
dc.contributor.authorLiu, Z-
dc.contributor.authorChen, HY-
dc.date.accessioned2015-09-18T06:50:09Z-
dc.date.available2015-09-18T06:50:09Z-
dc.date.issued2015-
dc.identifier.citationOncotarget, 2015, v. 6 n. 31, p. 30939-30956-
dc.identifier.issn1949-2553-
dc.identifier.urihttp://hdl.handle.net/10722/218681-
dc.description.abstractThe synthetic curcumin analog B5 is a potent inhibitor of thioredoxin reductase (TrxR) that has potential anticancer effects. The molecular mechanism underlying B5 as an anticancer agent is not yet fully understood. In this study, we report that B5 induces apoptosis in two human cervical cancer cell lines, CaSki and SiHa, as evidenced by the downregulation of XIAP, activation of caspases and cleavage of PARP. The involvement of the mitochondrial pathway in B5-induced apoptosis was suggested by the dissipation of mitochondrial membrane potential and increased expression of pro-apoptotic Bcl-2 family proteins. In B5-treated cells, TrxR activity was markedly inhibited with concomitant accumulation of oxidized thioredoxin, increased formation of reactive oxygen species (ROS), and activation of ASK1 and its downstream regulatory target p38/JNK. B5-induced apoptosis was significantly inhibited in the presence of N-acetyl-l-cysteine. Microscopic examination of B5-treated cells revealed increased presence of cytoplasmic vacuoles. The ability of B5 to activate autophagy in cells was subsequently confirmed by cell staining with acridine orange, accumulation of LC3-II, and measurement of autophagic flux. Unlike B5-induced apoptosis, autophagy induced by B5 is not ROS-mediated but a role for the AKT and AMPK signaling pathways is implied. In SiHa cells but not CaSki cells, B5-induced apoptosis was promoted by autophagy. These data suggest that the anticarcinogenic effects of B5 is mediated by complex interplay between cellular mechanisms governing redox homeostasis, apoptosis and autophagy.-
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.subjectApoptosis-
dc.subjectCervical cancer-
dc.subjectCurcumin analog-
dc.subjectThioredoxin reductase-
dc.titleB5, a thioredoxin reductase inhibitor, induces apoptosis in human cervical cancer cells by suppressing the thioredoxin system, disrupting mitochondrion-dependent pathways and triggering autophagy-
dc.typeArticle-
dc.identifier.emailWong, NS: nswong@hku.hk-
dc.identifier.authorityWong, NS=rp00340-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.18632/oncotarget.5132-
dc.identifier.pmid26439985-
dc.identifier.scopuseid_2-s2.0-84945569605-
dc.identifier.hkuros250468-
dc.identifier.volume6-
dc.identifier.issue31-
dc.identifier.spage30939-
dc.identifier.epage30956-
dc.identifier.isiWOS:000363185200052-
dc.publisher.placeUnited States-

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