ATP-dependent activity and mitochondrial localization of drug efflux pumps in doxorubicin-resistant breast cancer cells.

Abstract : BACKGROUND: We hypothesized that, among the mechanisms of drug-resistance acquired by doxorubicin (DOX)-resistant breast cancer cells to maintain cell survival, ATP-dependent drug efflux pumps could be expressed in their mitochondrial membranes and this might limit the accumulation of DOX in this subcellular compartment in relation to mitochondrial ATP production. Methods/results Mitochondrial DOX accumulation: the presence and the activity of mitochondrial efflux pumps and their relationship with mitochondrial ATP synthesis were analyzed in DOX-resistant (MCF-7doxR) and -sensitive (MCF-7S) breast cancer cells. Mitochondrial accumulation of DOX (autofluorescence) was decreased when ATP was produced, but only in MCF-7doxR. In these DOX-resistant cells, breast cancer resistance protein (BCRP) and multidrug resistance-associated protein (MRP1) were expressed and localized in mitochondria (confocal microscopy and confocal spectral imaging studies). In addition, mitochondrial accumulation of DOX was increased by BCRP and MRP1 inhibitors and, to a lower extent, by the mitochondrial ATP synthase inhibitor, oligomycin, in MCF-7doxR. CONCLUSIONS: Both BCRP and MRP1 were localized in mitochondria and participated to the reduction of mitochondrial accumulation of DOX in MCF-7doxR. This process was partly dependent of mitochondrial ATP synthesis. GENERAL SIGNIFICANCE: The present study provides novel insights in the involvement of mitochondria in the underlying mechanisms of DOX-resistance in breast cancer cells.
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https://hal-univ-tours.archives-ouvertes.fr/hal-01477144
Contributeur : Martin Soucé <>
Soumis le : lundi 27 février 2017 - 09:19:58
Dernière modification le : lundi 2 juillet 2018 - 16:20:15

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Julie Dartier, Elsa Lemaitre, Igor Chourpa, Caroline Goupille, Stéphane Servais, et al.. ATP-dependent activity and mitochondrial localization of drug efflux pumps in doxorubicin-resistant breast cancer cells.. BBA - General Subjects, Elsevier, 2017, 〈http://www.sciencedirect.com/science/article/pii/S0304416517300673〉. 〈10.1016/j.bbagen.2017.02.019〉. 〈hal-01477144〉

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