Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, United States; East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, United States.
Human Performance Laboratory, Department of Kinesiology, East Carolina University, Greenville, United States.
Biochim Biophys Acta Bioenerg. 2022 Nov 1;1863(8):148915. doi: 10.1016/j.bbabio.2022.148915. Epub 2022 Sep 2.
Although the development of chemoresistance is multifactorial, active chemotherapeutic efflux driven by upregulations in ATP binding cassette (ABC) transporters are commonplace. Chemotherapeutic efflux pumps, like ABCB1, couple drug efflux to ATP hydrolysis and thus potentially elevate cellular demand for ATP resynthesis. Elevations in both mitochondrial content and cellular respiration are common phenotypes accompanying many models of cancer cell chemoresistance, including those dependent on ABCB1. The present study set out to characterize potential mitochondrial remodeling commensurate with ABCB1-dependent chemoresistance, as well as investigate the impact of ABCB1 activity on mitochondrial respiratory kinetics. To do this, comprehensive bioenergetic phenotyping was performed across ABCB1-dependent chemoresistant cell models and compared to chemosensitive controls. In doxorubicin (DOX) resistant ovarian cancer cells, the combination of both increased mitochondrial content and enhanced respiratory complex I (CI) boosted intrinsic oxidative phosphorylation (OXPHOS) power output. With respect to ABCB1, acute ABCB1 inhibition partially normalized intact basal mitochondrial respiration between chemosensitive and chemoresistant cells, suggesting that active ABCB1 contributes to mitochondrial remodeling in favor of enhanced OXPHOS. Interestingly, while enhanced OXPHOS power output supported ABCB1 drug efflux when DOX was present, in the absence of chemotherapeutic stress, enhanced OXPHOS power output was associated with reduced tumorigenicity.
尽管化疗耐药性的发展是多因素的，但由 ATP 结合盒（ABC）转运蛋白上调驱动的活性化疗药物外排是很常见的。化疗药物外排泵，如 ABCB1，将药物外排与 ATP 水解偶联，从而可能增加细胞对 ATP 再合成的需求。线粒体含量和细胞呼吸的增加是许多癌症细胞化疗耐药模型的常见表型，包括那些依赖于 ABCB1 的模型。本研究旨在描述与 ABCB1 依赖性化疗耐药相关的潜在线粒体重塑，并研究 ABCB1 活性对线粒体呼吸动力学的影响。为此，在依赖于 ABCB1 的化疗耐药细胞模型中进行了全面的生物能量表型分析，并与化疗敏感对照进行了比较。在多柔比星（DOX）耐药卵巢癌细胞中，线粒体含量增加和呼吸复合物 I（CI）增强同时提高了内在氧化磷酸化（OXPHOS）的功率输出。就 ABCB1 而言，急性 ABCB1 抑制部分使化疗敏感和耐药细胞之间完整的基础线粒体呼吸正常化，这表明活跃的 ABCB1 有助于支持增强的 OXPHOS 的线粒体重塑。有趣的是，虽然当 DOX 存在时增强的 OXPHOS 功率输出支持 ABCB1 药物外排，但在没有化疗应激的情况下，增强的 OXPHOS 功率输出与降低的致瘤性相关。
