Molecular analysis of the massive GSH transport mechanism mediated by the human Multidrug Resistant Protein 1/ABCC1
In: ISSN: 2045-2322, 2020
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Zugriff:
International audience ; The transporter Multidrug Resistance Protein 1 (MRP1, ABCC1) is implicated in multidrug resistant (MDR) phenotype of cancer cells. Glutathione (GSH) plays a key role in MRP1 transport activities. In addition, a ligand-stimulated GSH transport which triggers the death of cells overexpressing MRP1, by collateral sensitivity (CS), has been described. This CS could be a way to overcome the poor prognosis for patients suffering from a chemoresistant cancer. The molecular mechanism of such massive GSH transport and its connection to the other transport activities of MRP1 are unknown. In this context, we generated MRP1/MRP2 chimeras covering different regions, MRP2 being a close homolog that does not trigger CS. The one encompassing helices 16 and 17 led to the loss of CS and MDR phenotype without altering basal GSH transport. Within this region, the sole restoration of the original G1228 (D1236 in MRP2) close to the extracellular loop between the two helices fully rescued the CS (massive GSH efflux and cell death) but not the MDR phenotype. The flexibility of that loop and the binding of a CS agent like verapamil could favor a particular conformation for the massive transport of GSH, not related to other transport activities of MRP1.
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Molecular analysis of the massive GSH transport mechanism mediated by the human Multidrug Resistant Protein 1/ABCC1
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Autor/in / Beteiligte Person: | Nasr, Rachad ; Lorendeau, Doriane ; Khonkarn, Ruttiros ; Dury, Lauriane ; Pérès, Basile ; Boumendjel, Ahcène ; Cortay, Jean-Claude ; Falson, Pierre ; Chaptal, Vincent ; Baubichon-Cortay, Hélène ; Drug Resistance and Membrane Proteins group Lyon ; Institut de biologie et chimie des protéines Lyon (IBCP) ; Université Claude Bernard Lyon 1 (UCBL) ; Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL) ; Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS) ; Chiang Mai University (CMU) ; Département de pharmacochimie moléculaire (DPM) ; Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA) ; Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL) ; Centre Léon Bérard Lyon -Université Claude Bernard Lyon 1 (UCBL) ; Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) ; We thank the French Ministère de l’Education Nationale, de l’Enseignement Supérieur et de la Recherche and the Ligue Nationale contre le Cancer for the doctoral fellowship accorded to Lauriane Dury, Rachad Nasr and Doriane Lorendeau. Financial support of this work was provided by grants from the French ANR and Hungarian NIH (2010-INT-1101-01) and from the Ligue Nationale contre le Cancer (Team certified Ligue 2012 and Comité du Rhône 2016-2017). |
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Zeitschrift: | ISSN: 2045-2322, 2020 |
Veröffentlichung: | HAL CCSD ; Nature Publishing Group, 2020 |
Medientyp: | academicJournal |
DOI: | 10.1038/s41598-020-64400-x |
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