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

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, Hugo Arias-Pulido, Karatatiwant S. Sidhu, Brian Silverstrim, Yoonseok Kam, Shana Kelley, Mark Pereira, Susan E. Bates, Janice Y. Bunn, Steven N. Fiering, Dwight E. Matthews, Robert W. Robey, Domink Stich, Angelo D’Alessandro () and Mercedes Rincon ()
Additional contact information
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
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

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23071-6

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