title: ATP-dependent activity and mitochondrial localization of drug efflux pumps in doxorubicin-resistant breast cancer cells.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  The present study provides novel insights in the involvement of mitochondria in the underlying mechanisms of DOX-resistance in breast cancer cells.
authors.affiliation: INSERM UMR1069, "Nutrition, Croissance et Cancer", Tours, France; Université François Rabelais, Tours, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Dartier
authors.affiliation: INSERM UMR1069, "Nutrition, Croissance et Cancer", Tours, France.
authors.forename: Elsa
authors.initials: E
authors.lastname: Lemaitre
authors.affiliation: Université François Rabelais, Tours, France; EA 6295 "Nanomédicaments et Nanosondes", Tours, France; UFR Sciences Pharmaceutiques, Tours, France.
authors.forename: Igor
authors.initials: I
authors.lastname: Chourpa
authors.affiliation: INSERM UMR1069, "Nutrition, Croissance et Cancer", Tours, France; CHRU Bretonneau, Tours, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Goupille
authors.affiliation: INSERM UMR1069, "Nutrition, Croissance et Cancer", Tours, France; Université François Rabelais, Tours, France; IUT, Tours, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Servais
authors.affiliation: INSERM UMR1069, "Nutrition, Croissance et Cancer", Tours, France; Université François Rabelais, Tours, France; UFR Sciences Pharmaceutiques, Tours, France.
authors.forename: Stéphan
authors.initials: S
authors.lastname: Chevalier
authors.affiliation: INSERM UMR1069, "Nutrition, Croissance et Cancer", Tours, France; Université François Rabelais, Tours, France; UFR Sciences Pharmaceutiques, Tours, France. Electronic address: karine.maheo@univ-tours.fr.
authors.forename: Karine
authors.initials: K
authors.lastname: Mahéo
authors.affiliation: INSERM UMR1069, "Nutrition, Croissance et Cancer", Tours, France; Université François Rabelais, Tours, France; UFR Sciences Pharmaceutiques, Tours, France. Electronic address: jean-francois.dumas@univ-tours.fr.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Dumas
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004317:Doxorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008928:Mitochondria / Q000378:metabolism*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D000255:Adenosine Triphosphate; D004317:Doxorubicin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; C116614:ABCG2 protein, human; C421109:multidrug resistance-associated protein 1
keywords: Breast cancer; Breast cancer resistance protein; Chemoresistance; Mitochondrial ATP synthesis; Multidrug resistance-associated protein