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dc.contributor.authorLok, Hiu Chuen
dc.contributor.authorSahni, Sumit
dc.contributor.authorJansson, Patric J
dc.contributor.authorKovacevic, Zaklina
dc.contributor.authorHawkins, Clare L
dc.contributor.authorRichardson, Des R
dc.date.accessioned2021-04-30T00:43:09Z
dc.date.available2021-04-30T00:43:09Z
dc.date.issued2016
dc.identifier.issn0021-9258en_US
dc.identifier.doi10.1074/jbc.M116.763714en_US
dc.identifier.urihttp://hdl.handle.net/10072/404046
dc.description.abstractNitric oxide (NO) is integral to macrophage cytotoxicity against tumors due to its ability to induce iron release from cancer cells. However, the mechanism for how activated macrophages protect themselves from endogenous NO remains unknown. We previously demonstrated by using tumor cells that glutathione S-transferase P1 (GSTP1) sequesters NO as dinitrosyl-dithiol iron complexes (DNICs) and inhibits NO-mediated iron release from cells via the transporter multidrug resistance protein 1 (MRP1/ABCC1). These prior studies also showed that MRP1 and GSTP1 protect tumor cells against NO cytotoxicity, which parallels their roles in defending cancer cells from cytotoxic drugs. Considering this, and because GSTP1 and MRP1 are up-regulated during macrophage activation, this investigation examined whether this NO storage/transport system protects macrophages against endogenous NO cytotoxicity in two well characterized macrophage cell types (J774 and RAW 264.7). MRP1 expression markedly increased upon macrophage activation, and the role of MRP1 in NO-induced Fe release was demonstrated by Mrp1 siRNA and the MRP1 inhibitor, MK571, which inhibited NO-mediated iron efflux. Furthermore, Mrp1 silencing increased DNIC accumulation in macrophages, indicating a role for MRP1 in transporting DNICs out of cells. In addition, macrophage Fe release was enhanced by silencing Gstp1, suggesting GSTP1 was responsible for DNIC binding/storage. Viability studies demonstrated that GSTP1 and MRP1 protect activated macrophages from NO cytotoxicity. This was confirmed by silencing nuclear factor-erythroid 2-related factor 2 (Nrf2), which decreased MRP1 and GSTP1 expression, concomitant with reduced Fe release and macrophage survival. Together, these results demonstrate a mechanism by which macrophages protect themselves against NO cytotoxicity. 59 59 59en_US
dc.description.peerreviewedYesen_US
dc.languageEnglishen_US
dc.publisherElsevieren_US
dc.relation.ispartofpagefrom27042en_US
dc.relation.ispartofpageto27061en_US
dc.relation.ispartofissue53en_US
dc.relation.ispartofjournalJournal of Biological Chemistryen_US
dc.relation.ispartofvolume291en_US
dc.subject.fieldofresearchChemical Sciencesen_US
dc.subject.fieldofresearchBiological Sciencesen_US
dc.subject.fieldofresearchMedical and Health Sciencesen_US
dc.subject.fieldofresearchcode03en_US
dc.subject.fieldofresearchcode06en_US
dc.subject.fieldofresearchcode11en_US
dc.subject.keywordsScience & Technologyen_US
dc.subject.keywordsLife Sciences & Biomedicineen_US
dc.subject.keywordsBiochemistry & Molecular Biologyen_US
dc.subject.keywordsGLUTATHIONE-S-TRANSFERASEen_US
dc.subject.keywordsTRANSCRIPTION FACTOR NRF2en_US
dc.titleA Nitric Oxide Storage and Transport System That Protects Activated Macrophages from Endogenous Nitric Oxide Cytotoxicityen_US
dc.typeJournal articleen_US
dc.type.descriptionC1 - Articlesen_US
dcterms.bibliographicCitationLok, HC; Sahni, S; Jansson, PJ; Kovacevic, Z; Hawkins, CL; Richardson, DR, A Nitric Oxide Storage and Transport System That Protects Activated Macrophages from Endogenous Nitric Oxide Cytotoxicity, Journal of Biological Chemistry, 2016, 291 (53), pp. 27042-27061en_US
dcterms.licensehttps://creativecommons.org/licenses/by/4.0/en_US
dc.date.updated2021-04-30T00:40:26Z
dc.description.versionAccepted Manuscript (AM)en_US
gro.rights.copyright© 2016 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A. 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.en_US
gro.hasfulltextFull Text
gro.griffith.authorRichardson, Des R.


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