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dc.contributor.authorA. J. Smith, Robinen_US
dc.contributor.authorA. Salvatore, Brianen_US
dc.contributor.authorCerny, Jirien_US
dc.contributor.authorCoster, Marken_US
dc.contributor.authorDong, Lan-fengen_US
dc.contributor.authorDyason, Jeffreyen_US
dc.contributor.authorHernandez-Esquivel, Luzen_US
dc.contributor.authorJ. A. Jameson, Victoriaen_US
dc.contributor.authorK. Witting, Paulen_US
dc.contributor.authorKluckova, Katarinaen_US
dc.contributor.authorLedvina, Miroslaven_US
dc.contributor.authorMahdavian, Elaheen_US
dc.contributor.authorMarín-Hernandez, Alvaroen_US
dc.contributor.authorMoreno-Sanchez, Rafaelen_US
dc.contributor.authorNeuzil, Jirien_US
dc.contributor.authorRalph, Stephenen_US
dc.contributor.authorRodríguez-Enríquez, Saraen_US
dc.contributor.authorRohlena, Jakuben_US
dc.contributor.authorStantic, Belaen_US
dc.contributor.authorStursa, Janen_US
dc.contributor.authorTilly, Daviden_US
dc.contributor.authorTruksa, Jaroslaven_US
dc.contributor.editorMartha Fedoren_US
dc.date.accessioned2017-04-04T14:44:14Z
dc.date.available2017-04-04T14:44:14Z
dc.date.issued2011en_US
dc.date.modified2011-10-19T07:26:27Z
dc.identifier.issn00219258en_US
dc.identifier.doi10.1074/jbc.M110.186643en_AU
dc.identifier.urihttp://hdl.handle.net/10072/39853
dc.description.abstractMitochondrial complex II (CII) has been recently identified as a novel target for anti-cancer drugs. Mitochondrially targeted vitamin E succinate (MitoVES) is modified so that it is preferentially localized to mitochondria, greatly enhancing its pro-apoptotic and anti-cancer activity. Using genetically manipulated cells, MitoVES caused apoptosis and generation of reactive oxygen species (ROS) in CII-proficient malignant cells but not their CII-dysfunctional counterparts. MitoVES inhibited the succinate dehydrogenase (SDH) activity of CII with IC50 of 80 孬 whereas the electron transfer from CII to CIII was inhibited with IC50 of 1.5 孮 The agent had no effect either on the enzymatic activity of CI or on electron transfer from CI to CIII. Over 24 h, MitoVES caused stabilization of the oxygen-dependent destruction domain of HIF1a fused to GFP, indicating promotion of the state of pseudohypoxia. Molecular modeling predicted the succinyl group anchored into the proximal CII ubiquinone (UbQ)-binding site and successively reduced interaction energies for serially shorter phytyl chain homologs of MitoVES correlated with their lower effects on apoptosis induction, ROS generation, and SDH activity. Mutation of the UbQ-binding Ser68 within the proximal site of the CII SDHC subunit (S68A or S68L) suppressed both ROS generation and apoptosis induction by MitoVES. In vivo studies indicated that MitoVES also acts by causing pseudohypoxia in the context of tumor suppression. We propose that mitochondrial targeting of VES with an 11-carbon chain localizes the agent into an ideal position across the interface of the mitochondrial inner membrane and matrix, optimizing its biological effects as an anti-cancer drug.en_US
dc.description.peerreviewedYesen_US
dc.description.publicationstatusYesen_AU
dc.format.extent1047134 bytes
dc.format.mimetypeapplication/pdf
dc.languageEnglishen_US
dc.language.isoen_AU
dc.publisherAmerican Society for Biochemistry and Molecular Biology, Inc.en_US
dc.publisher.placeUnited Statesen_US
dc.relation.ispartofstudentpublicationNen_AU
dc.relation.ispartofpagefrom3717en_US
dc.relation.ispartofpageto3728en_US
dc.relation.ispartofissue5en_AU
dc.relation.ispartofjournalJournal of Biological Chemistryen_US
dc.relation.ispartofvolume286en_US
dc.rights.retentionYen_AU
dc.subject.fieldofresearchMedical Microbiology not elsewhere classifieden_US
dc.subject.fieldofresearchcode110899en_US
dc.titleMitochondrial Targeting of Vitamin E Succinate Enhances Its Pro-apoptotic and Anti-cancer Activity via Mitochondrial: Complex IIen_US
dc.typeJournal articleen_US
dc.type.descriptionC1 - Peer Reviewed (HERDC)en_US
dc.type.codeC - Journal Articlesen_US
gro.facultyGriffith Health, School of Medical Scienceen_US
gro.rights.copyrightThis research was originally published in Journal of Biological Chemistry (JBC). Lan-Feng Dong etc, Mitochondrial Targeting of Vitamin E Succinate Enhances Its Pro-apoptotic and Anti-cancer Activity via Mitochondrial: Complex II, Journal of Biological Chemistry (JBC), 2011; Vol. 286(5), pp. 3717-3728. Copyright the American Society for Biochemistry and Molecular Biology. This is the author-manuscript version of this paper. Reproduced in accordance with the copyright policy of the publisher. Please refer to the journal's website for access to the definitve version.en_AU
gro.date.issued2011
gro.hasfulltextFull Text


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