ATP-dependent activity and mitochondrial localization of drug efflux pumps in doxorubicin-resistant breast cancer cells
ATP-dependent activity and mitochondrial localization of drug efflux pumps in doxorubicin-resistant breast cancer cells
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DOI：
10.1016/j.bbagen.2017.02.019
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发表时间：
2017-05-01
影响因子：
3
通讯作者：
Dumas, Jean-Francois
中科院分区：
文献类型：
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作者：
Dartier, Julie;Lemaitre, Elsa;Dumas, Jean-Francois
背景资料：我们假设，在多柔比星（DOX）抗性乳腺癌细胞获得的维持细胞存活的耐药性机制中，ATP依赖性药物外排泵可以在其线粒体膜中表达，这可能限制DOX在该亚细胞区室中与线粒体ATP产生相关的积累。在DOX抗性（MCF-7 dox（R））和敏感性（MCF-7（S））乳腺癌细胞中分析线粒体外排泵的存在和活性及其与线粒体ATP合成的关系。当ATP产生时，DOX的线粒体积累（自发荧光）减少，但仅在MCF-7 dox（R）中。在这些DOX耐药细胞中，乳腺癌耐药蛋白（BCRP）和多药耐药相关蛋白（MRP 1）表达并定位于线粒体中（共聚焦显微镜和共聚焦光谱成像研究）。此外，BCRP和MRP 1抑制剂可增加MCF-7 dox（R）中DOX的线粒体蓄积，线粒体ATP合成酶抑制剂寡霉素也可增加DOX的线粒体蓄积（程度较低）。结论：BCRP和MRP 1均定位于MCF-7 dox（R）中的线粒体，并参与DOX在MCF-7 dox（R）线粒体蓄积的减少。这一过程部分依赖于线粒体ATP的合成。一般意义。本研究提供了新的见解线粒体参与乳腺癌细胞的DOX耐药的潜在机制。(C)2017爱思唯尔B. V.保留所有权利。
Background: We hypothesized that, among the mechanisms of drug-resistance acquired by doxorubicin (DOX)-resistant breast cancer cells to maintain cell survival, ATP-dependent drug efflux pumps could be expressed in their mitochondrial membranes and this might limit the accumulation of DOX in this subcellular compartment in relation to mitochondrial ATP production.Methods/results: Mitochondrial DOX accumulation: the presence and the activity of mitochondrial efflux pumps and their relationship with mitochondrial ATP synthesis were analyzed in DOX-resistant (MCF-7dox(R)) and-sensitive (MCF-7(S)) breast cancer cells. Mitochondrial accumulation of DOX (autofluorescence) was decreased when ATP was produced, but only in MCF-7dox(R). In these DOX-resistant cells, breast cancer resistance protein (BCRP) and multidrug resistance-associated protein (MRP1) were expressed and localized in mitochondria (confocal microscopy and confocal spectral imaging studies). In addition, mitochondrial accumulation of DOX was increased by BCRP and MRP1 inhibitors and, to a lower extent, by the mitochondrial ATP synthase inhibitor, oligomycin, in MCF-7dox(R).Conclusions: Both BCRP and MRP1 were localized in mitochondria and participated to the reduction of mitochondrial accumulation of DOX in MCF-7dox(R). This process was partly dependent of mitochondrial ATP synthesis. General Significance. The present study provides novel insights in the involvement of mitochondria in the underlying mechanisms of DOX-resistance in breast cancer cells. (C) 2017 Elsevier B.V. All rights reserved.