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dc.contributor.authorLudlow, Melanie J
dc.contributor.authorGaunt, Hannah J
dc.contributor.authorRubaiy, Hussein N
dc.contributor.authorMusialowski, Katie E
dc.contributor.authorBlythe, Nicola M
dc.contributor.authorVasudev, Naveen S
dc.contributor.authorMuraki, Katsuhiko
dc.contributor.authorBeech, David J
dc.date.accessioned2020-02-13T23:48:28Z
dc.date.available2020-02-13T23:48:28Z
dc.date.issued2017
dc.identifier.issn1083-351X
dc.identifier.doi10.1074/jbc.M116.755678
dc.identifier.urihttp://hdl.handle.net/10072/391436
dc.description.abstract(−)-Englerin A ((−)-EA) has a rapid and potent cytotoxic effect on several types of cancer cell that is mediated by plasma membrane ion channels containing transient receptor potential canonical 4 (TRPC4) protein. Because these channels are Ca2+-permeable, it was initially thought that the cytotoxicity arose as a consequence of Ca2+ overload. Here we show that this is not the case and that the effect of (−)-EA is mediated by a heteromer of TRPC4 and TRPC1 proteins. Both TRPC4 and TRPC1 were required for (−)-EA cytotoxicity; however, although TRPC4 was necessary for the (−)-EA-evoked Ca2+ elevation, TRPC1 was not. TRPC1 either had no role or was a negative regulator of Ca2+ entry. By contrast, both TRPC4 and TRPC1 were necessary for monovalent cation entry evoked by (−)-EA, and (−)-EA-evoked cell death was dependent upon entry of the monovalent cation Na+. We therefore hypothesized that Na+/K+-ATPase might act protectively by counteracting the Na+ load resulting from sustained Na+ entry. Indeed, inhibition of Na+/K+-ATPase by ouabain potently and strongly increased (−)-EA-evoked cytotoxicity. The data suggest that (−)-EA achieves cancer cell cytotoxicity by inducing sustained Na+ entry through heteromeric TRPC1/TRPC4 channels and that the cytotoxic effect of (−)-EA can be potentiated by Na+/K+-ATPase inhibition.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherAmerican Society for Biochemistry and Molecular Biology
dc.relation.ispartofpagefrom723
dc.relation.ispartofpageto731
dc.relation.ispartofissue2
dc.relation.ispartofjournalJournal of Biological Chemistry
dc.relation.ispartofvolume292
dc.subject.fieldofresearchChemical Sciences
dc.subject.fieldofresearchBiological Sciences
dc.subject.fieldofresearchMedical and Health Sciences
dc.subject.fieldofresearchcode03
dc.subject.fieldofresearchcode06
dc.subject.fieldofresearchcode11
dc.subject.keywordsScience & Technology
dc.subject.keywordsLife Sciences & Biomedicine
dc.subject.keywordsBiochemistry & Molecular Biology
dc.subject.keywordsNONSELECTIVE CATION CHANNELS
dc.subject.keywordsRENAL-CELL CARCINOMA
dc.title(-)-Englerin A-evoked Cytotoxicity Is Mediated by Na+ Influx and Counteracted by Na+/K+-ATPase
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationLudlow, MJ; Gaunt, HJ; Rubaiy, HN; Musialowski, KE; Blythe, NM; Vasudev, NS; Muraki, K; Beech, DJ, (-)-Englerin A-evoked Cytotoxicity Is Mediated by Na+ Influx and Counteracted by Na+/K+-ATPase, Journal of Biological Chemistry, 2017, 292 (2), pp. 723-731
dcterms.licensehttp://creativecommons.org/licenses/by/4.0
dc.date.updated2020-02-13T23:46:16Z
dc.description.versionVersion of Record (VoR)
gro.rights.copyright© 2016 by The American Society for Biochemistry and Molecular Biology, Inc. This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
gro.hasfulltextFull Text
gro.griffith.authorMuraki, Katsuhiko


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