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Article: Intracellular Iron Chelation by a Novel Compound, C7, Reactivates Epstein–Barr Virus (EBV) Lytic Cycle via the ERK-Autophagy Axis in EBV-Positive Epithelial Cancers

TitleIntracellular Iron Chelation by a Novel Compound, C7, Reactivates Epstein–Barr Virus (EBV) Lytic Cycle via the ERK-Autophagy Axis in EBV-Positive Epithelial Cancers
Authors
Keywordsiron chelation
Epstein–Barr virus
lytic cycle
gastric carcinoma
nasopharyngeal carcinoma
Issue Date2018
PublisherMDPI AG. The Journal's web site is located at http://www.mdpi.com/journal/cancers/
Citation
Cancers, 2018, v. 10 n. 12, p. article no. 505 How to Cite?
AbstractPharmaceutical reactivation of lytic cycle of Epstein–Barr virus (EBV) represents a potential therapeutic strategy against EBV-associated epithelial malignancies, e.g., gastric carcinoma (GC) and nasopharyngeal carcinoma (NPC). A novel lytic-inducing compound, C7, which exhibits structural similarity to Di-2-Pyridyl Ketone 4, 4-Dimethyl-3-Thiosemicarbazone (Dp44mT), a known chelator of intracellular iron, is found to reactivate EBV lytic cycle in GC and NPC. This study aims to investigate the role of intracellular iron chelation by C7 and other iron chelators in lytic reactivation of EBV in GC and NPC. Testing of six structural analogs of C7 revealed only those which have high affinity towards transition metals could induce EBV lytic cycle. Precomplexing C7 and iron chelators to iron prior to treatment of the cells abolished EBV lytic reactivation. Though hypoxia signaling pathway was activated, it was not the only pathway associated with EBV reactivation. Specifically, C7 and iron chelators initiated autophagy by activating extracellular signal-regulated kinase (ERK1/2) to reactivate EBV lytic cycle since autophagy and EBV lytic reactivation were abolished in cells treated with ERK1/2 blockers whilst inhibition of autophagy by 3-Methyladenine (3-MA) and atg5 knockdown significantly abolished EBV lytic reactivation. In summary, we discovered a novel mechanism of reactivation of the EBV lytic cycle through intracellular iron chelation and induction of ERK-autophagy axis in EBV-positive epithelial malignancies, raising the question whether clinically available iron chelators can be incorporated into existing therapeutic regimens to treat these cancers.
Persistent Identifierhttp://hdl.handle.net/10722/279389
ISSN
2017 Impact Factor: 5.326
2015 SCImago Journal Rankings: 1.630

 

DC FieldValueLanguage
dc.contributor.authorYIU, SPT-
dc.contributor.authorHui, KF-
dc.contributor.authorChoi, CK-
dc.contributor.authorKao, RYT-
dc.contributor.authorMA, CW-
dc.contributor.authorYang, D-
dc.contributor.authorChiang, AKS-
dc.date.accessioned2019-11-01T07:16:23Z-
dc.date.available2019-11-01T07:16:23Z-
dc.date.issued2018-
dc.identifier.citationCancers, 2018, v. 10 n. 12, p. article no. 505-
dc.identifier.issn2072-6694-
dc.identifier.urihttp://hdl.handle.net/10722/279389-
dc.description.abstractPharmaceutical reactivation of lytic cycle of Epstein–Barr virus (EBV) represents a potential therapeutic strategy against EBV-associated epithelial malignancies, e.g., gastric carcinoma (GC) and nasopharyngeal carcinoma (NPC). A novel lytic-inducing compound, C7, which exhibits structural similarity to Di-2-Pyridyl Ketone 4, 4-Dimethyl-3-Thiosemicarbazone (Dp44mT), a known chelator of intracellular iron, is found to reactivate EBV lytic cycle in GC and NPC. This study aims to investigate the role of intracellular iron chelation by C7 and other iron chelators in lytic reactivation of EBV in GC and NPC. Testing of six structural analogs of C7 revealed only those which have high affinity towards transition metals could induce EBV lytic cycle. Precomplexing C7 and iron chelators to iron prior to treatment of the cells abolished EBV lytic reactivation. Though hypoxia signaling pathway was activated, it was not the only pathway associated with EBV reactivation. Specifically, C7 and iron chelators initiated autophagy by activating extracellular signal-regulated kinase (ERK1/2) to reactivate EBV lytic cycle since autophagy and EBV lytic reactivation were abolished in cells treated with ERK1/2 blockers whilst inhibition of autophagy by 3-Methyladenine (3-MA) and atg5 knockdown significantly abolished EBV lytic reactivation. In summary, we discovered a novel mechanism of reactivation of the EBV lytic cycle through intracellular iron chelation and induction of ERK-autophagy axis in EBV-positive epithelial malignancies, raising the question whether clinically available iron chelators can be incorporated into existing therapeutic regimens to treat these cancers.-
dc.languageeng-
dc.publisherMDPI AG. The Journal's web site is located at http://www.mdpi.com/journal/cancers/-
dc.relation.ispartofCancers-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectiron chelation-
dc.subjectEpstein–Barr virus-
dc.subjectlytic cycle-
dc.subjectgastric carcinoma-
dc.subjectnasopharyngeal carcinoma-
dc.titleIntracellular Iron Chelation by a Novel Compound, C7, Reactivates Epstein–Barr Virus (EBV) Lytic Cycle via the ERK-Autophagy Axis in EBV-Positive Epithelial Cancers-
dc.typeArticle-
dc.identifier.emailHui, KF: kfhui@hku.hk-
dc.identifier.emailKao, RYT: rytkao@hkucc.hku.hk-
dc.identifier.emailYang, D: yangdan@hku.hk-
dc.identifier.emailChiang, AKS: chiangak@hku.hk-
dc.identifier.authorityKao, RYT=rp00481-
dc.identifier.authorityYang, D=rp00825-
dc.identifier.authorityChiang, AKS=rp00403-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.3390/cancers10120505-
dc.identifier.scopuseid_2-s2.0-85058466427-
dc.identifier.hkuros308606-
dc.identifier.volume10-
dc.identifier.issue12-
dc.identifier.spagearticle no. 505-
dc.identifier.epagearticle no. 505-
dc.publisher.placeSwitzerland-

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