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Mitochondrial ATP fuels ABC transporter-mediated drug efflux in cancer chemoresistance.
Giddings, Emily L; Champagne, Devin P; Wu, Meng-Han; Laffin, Joshua M; Thornton, Tina M; Valenca-Pereira, Felipe; Culp-Hill, Rachel; Fortner, Karen A; Romero, Natalia; East, James; Cao, Phoebe; Arias-Pulido, Hugo; Sidhu, Karatatiwant S; Silverstrim, Brian; Kam, Yoonseok; Kelley, Shana; Pereira, Mark; Bates, Susan E; Bunn, Janice Y; Fiering, Steven N; Matthews, Dwight E; Robey, Robert W; Stich, Domink; D'Alessandro, Angelo; Rincon, Mercedes.
Afiliación
  • Giddings EL; Division of Immunobiology, Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
  • Champagne DP; Division of Immunobiology, Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
  • Wu MH; Department of Immunology and Microbiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
  • Laffin JM; Division of Immunobiology, Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
  • Thornton TM; Division of Immunobiology, Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
  • Valenca-Pereira F; Department of Immunology and Microbiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
  • Culp-Hill R; Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
  • Fortner KA; Division of Immunobiology, Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
  • Romero N; Cell Analysis Division, Agilent Technologies, Lexington, MA, USA.
  • East J; Division of Immunobiology, Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
  • Cao P; Department of Radiology, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
  • Arias-Pulido H; Department of Immunology and Microbiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
  • Sidhu KS; Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth College, Lebanon, NH, USA.
  • Silverstrim B; Department of Chemistry, University of Vermont, Burlington, VT, USA.
  • Kam Y; Division of Immunobiology, Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
  • Kelley S; Cell Analysis Division, Agilent Technologies, Lexington, MA, USA.
  • Pereira M; Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, Canada.
  • Bates SE; Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, Canada.
  • Bunn JY; Division of Hematology/Oncology, Columbia University Medical Center, New York City, NY, USA.
  • Fiering SN; Department of Medical Biostatistics, University of Vermont, Burlington, VT, USA.
  • Matthews DE; Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth College, Lebanon, NH, USA.
  • Robey RW; Department of Chemistry, University of Vermont, Burlington, VT, USA.
  • Stich D; Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • D'Alessandro A; Advanced Light Microscopy Core, Neurotechnology Center, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
  • Rincon M; Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA. Angelo.Dalessandro@cuanschutz.edu.
Nat Commun ; 12(1): 2804, 2021 05 14.
Article en En | MEDLINE | ID: mdl-33990571
Chemotherapy remains the standard of care for most cancers worldwide, however development of chemoresistance due to the presence of the drug-effluxing ATP binding cassette (ABC) transporters remains a significant problem. The development of safe and effective means to overcome chemoresistance is critical for achieving durable remissions in many cancer patients. We have investigated the energetic demands of ABC transporters in the context of the metabolic adaptations of chemoresistant cancer cells. Here we show that ABC transporters use mitochondrial-derived ATP as a source of energy to efflux drugs out of cancer cells. We further demonstrate that the loss of methylation-controlled J protein (MCJ) (also named DnaJC15), an endogenous negative regulator of mitochondrial respiration, in chemoresistant cancer cells boosts their ability to produce ATP from mitochondria and fuel ABC transporters. We have developed MCJ mimetics that can attenuate mitochondrial respiration and safely overcome chemoresistance in vitro and in vivo. Administration of MCJ mimetics in combination with standard chemotherapeutic drugs could therefore become an alternative strategy for treatment of multiple cancers.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Adenosina Trifosfato / Transportadoras de Casetes de Unión a ATP / Resistencia a Antineoplásicos / Mitocondrias Límite: Animals / Female / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Adenosina Trifosfato / Transportadoras de Casetes de Unión a ATP / Resistencia a Antineoplásicos / Mitocondrias Límite: Animals / Female / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido