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

• Published in: Nature communications Vol. 12; no. 1; pp. 2804 - 19
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.05.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/106; 13/109; 13/31; 13/89; 14; 14/19; 14/35; 14/5; 14/63; 38; 38/22; 42; 45; 49; 59; 631/67/1059/99; 631/67/2327; 64; 64/60; 82/58; 96/2; ABC transporter; ABC transporters; Adaptation; Adenosine Triphosphate - metabolism; Animals; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; ATP-Binding Cassette Transporters - metabolism; Biomimetic Materials - chemistry; Biomimetic Materials - pharmacology; Cancer; Cancer therapies; Cell Line, Tumor; Cell Respiration - drug effects; Cell Respiration - physiology; Chemoresistance; Chemotherapy; Doxorubicin - pharmacokinetics; Doxorubicin - pharmacology; Drug Resistance, Multiple - physiology; Drug Resistance, Neoplasm - physiology; Drugs; Efflux; Electron transport; Female; HSP40 Heat-Shock Proteins - deficiency; HSP40 Heat-Shock Proteins - metabolism; Humanities and Social Sciences; Humans; In Vitro Techniques; J protein; Mice; Mice, Inbred NOD; Mice, SCID; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; multidisciplinary; Neoplasms - drug therapy; Neoplasms - metabolism; Oxygen Consumption - drug effects; Respiration; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-23071-6

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. Drug efflux through ABC transporters is a common mechanism leading to chemoresistance in cancer. Here, the authors show that mitochondrial respiration provides ATP to allow ABC transporters activity so mitochondrial respiration inhibition overcomes chemoresistance in preclinical cancer models.