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dc.contributor.authorAl-Akra, Lina
dc.contributor.authorBae, Dong-Hun
dc.contributor.authorSahni, Sumit
dc.contributor.authorHuang, Michael LH
dc.contributor.authorPark, Kyung Chan
dc.contributor.authorLane, Darius JR
dc.contributor.authorJansson, Patric J
dc.contributor.authorRichardson, Des R
dc.date.accessioned2021-04-30T00:01:50Z
dc.date.available2021-04-30T00:01:50Z
dc.date.issued2018
dc.identifier.issn0021-9258en_US
dc.identifier.doi10.1074/jbc.M116.772699en_US
dc.identifier.urihttp://hdl.handle.net/10072/404042
dc.description.abstractMultidrug resistance (MDR) is a major obstacle in cancer treatment due to the ability of tumor cells to efflux chemotherapeutics via drug transporters (e.g. P-glycoprotein (Pgp; ABCB1)). Although the mechanism of Pgp-mediated drug efflux is known at the plasma membrane, the functional role of intracellular Pgp is unclear. Moreover, there has been intense focus on the tumor micro-environment as a target for cancer treatment. This investigation aimed to dissect the effects of tumor micro-environmental stress on subcellular Pgp expression, localization, and its role in MDR. These studies demonstrated that tumor microenvironment stressors (i.e. nutrient starvation, low glucose levels, reactive oxygen species, and hypoxia) induce Pgp-mediated drug resistance. This occurred by two mechanisms, where stressors induced 1) rapid Pgp internalization and redistribution via intracellular trafficking (within 1 h) and 2) hypoxia-inducible factor-1 expression after longer incubations (4 –24 h), which up-regulated Pgp and was accompanied by lysosomal biogenesis. These two mechanisms increased lysosomal Pgp and facilitated lysosomal accumulation of the Pgp substrate, doxorubicin, resulting in resistance. This was consistent with lysosomal Pgp being capable of transporting substrates into lysosomes. Hence, tumor micro-environmental stressors result in: 1) Pgp redistribution to lysosomes; 2) increased Pgp expression; 3) lysosomal biogenesis; and 4) potentiation of Pgp substrate transport into lysosomes. In contrast to doxorubicin, when stress stimuli increased lysosomal accumulation of the cytotoxic Pgp substrate, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), this resulted in the agent overcoming resistance. Overall, this investigation describes a novel approach to overcoming resistance in the stressful tumor micro-environment.en_US
dc.description.peerreviewedYesen_US
dc.languageEnglishen_US
dc.publisherElsevieren_US
dc.relation.ispartofpagefrom3562en_US
dc.relation.ispartofpageto3587en_US
dc.relation.ispartofissue10en_US
dc.relation.ispartofjournalJournal of Biological Chemistryen_US
dc.relation.ispartofvolume293en_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.keywordsISONICOTINOYL HYDRAZONE CLASSen_US
dc.subject.keywordsMULTIDRUG-RESISTANCEen_US
dc.titleTumor stressors induce two mechanisms of intracellular P-glycoprotein-mediated resistance that are overcome by lysosomal-targeted thiosemicarbazonesen_US
dc.typeJournal articleen_US
dc.type.descriptionC1 - Articlesen_US
dcterms.bibliographicCitationAl-Akra, L; Bae, D-H; Sahni, S; Huang, MLH; Park, KC; Lane, DJR; Jansson, PJ; Richardson, DR, Tumor stressors induce two mechanisms of intracellular P-glycoprotein-mediated resistance that are overcome by lysosomal-targeted thiosemicarbazones, Journal of Biological Chemistry, 2018, 293 (10), pp. 3562-3587en_US
dcterms.licensehttps://creativecommons.org/licenses/by/4.0/en_US
dc.date.updated2021-04-29T23:58:20Z
dc.description.versionVersion of Record (VoR)en_US
gro.rights.copyright© 2018 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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