Division of Immunobiology, Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
Department of Immunology and Microbiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
Nat Commun. 2021 May 14;12(1):2804. 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.
化疗仍然是全球大多数癌症的标准治疗方法，然而，由于存在药物外排的 ATP 结合盒（ABC）转运蛋白，产生化疗耐药性仍然是一个重大问题。开发安全有效的方法来克服化疗耐药性对于许多癌症患者实现持久缓解至关重要。我们已经研究了 ABC 转运蛋白在化疗耐药癌细胞代谢适应中的能量需求。在这里，我们表明 ABC 转运蛋白将线粒体衍生的 ATP 用作将药物从癌细胞中排出的能量来源。我们进一步证明，在化疗耐药癌细胞中，甲基化控制 J 蛋白（MCJ）（也称为 DnaJC15）的丧失，即线粒体呼吸的内源性负调节剂，可增强其从线粒体产生 ATP 的能力，并为 ABC 转运蛋白提供燃料。我们已经开发了 MCJ 模拟物，可减弱线粒体呼吸并在体外和体内安全地克服化疗耐药性。因此，MCJ 模拟物与标准化疗药物联合使用可能成为治疗多种癌症的替代策略。
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