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Mitochondrial ATP fuels ABC transporter-mediated drug efflux in cancer chemoresistance

Author

Listed:
  • Emily L. Giddings

    (University of Vermont)

  • Devin P. Champagne

    (University of Vermont)

  • Meng-Han Wu

    (University of Colorado Denver, Anschutz Medical Campus)

  • Joshua M. Laffin

    (University of Vermont)

  • Tina M. Thornton

    (University of Vermont)

  • Felipe Valenca-Pereira

    (University of Colorado Denver, Anschutz Medical Campus)

  • Rachel Culp-Hill

    (University of Colorado Denver, Anschutz Medical Campus)

  • Karen A. Fortner

    (University of Vermont)

  • Natalia Romero

    (Agilent Technologies)

  • James East

    (University of Vermont
    University of Vermont)

  • Phoebe Cao

    (University of Colorado Denver, Anschutz Medical Campus)

  • Hugo Arias-Pulido

    (Dartmouth College)

  • Karatatiwant S. Sidhu

    (University of Vermont)

  • Brian Silverstrim

    (University of Vermont)

  • Yoonseok Kam

    (Agilent Technologies)

  • Shana Kelley

    (University of Toronto)

  • Mark Pereira

    (University of Toronto)

  • Susan E. Bates

    (Columbia University Medical Center)

  • Janice Y. Bunn

    (University of Vermont)

  • Steven N. Fiering

    (Dartmouth College)

  • Dwight E. Matthews

    (University of Vermont)

  • Robert W. Robey

    (National Cancer Institute, National Institutes of Health)

  • Domink Stich

    (University of Colorado Denver, Anschutz Medical Campus)

  • Angelo D’Alessandro

    (University of Colorado Denver, Anschutz Medical Campus)

  • Mercedes Rincon

    (University of Vermont
    University of Colorado Denver, Anschutz Medical Campus)

Abstract

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.

Suggested Citation

  • Emily L. Giddings & Devin P. Champagne & Meng-Han Wu & Joshua M. Laffin & Tina M. Thornton & Felipe Valenca-Pereira & Rachel Culp-Hill & Karen A. Fortner & Natalia Romero & James East & Phoebe Cao & H, 2021. "Mitochondrial ATP fuels ABC transporter-mediated drug efflux in cancer chemoresistance," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23071-6
    DOI: 10.1038/s41467-021-23071-6
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    Cited by:

    1. Meng-Han Wu & Felipe Valenca-Pereira & Francesca Cendali & Emily L. Giddings & Catherine Pham-Danis & Michael C. Yarnell & Amanda J. Novak & Tonya M. Brunetti & Scott B. Thompson & Jorge Henao-Mejia &, 2024. "Deleting the mitochondrial respiration negative regulator MCJ enhances the efficacy of CD8+ T cell adoptive therapies in pre-clinical studies," Nature Communications, Nature, vol. 15(1), pages 1-22, December.

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