Structure and function of ABCG2-rich extracellular vesicles mediating multidrug resistance.
Structure and function of ABCG2-rich extracellular vesicles mediating multidrug resistance.
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DOI：
10.1371/journal.pone.0016007
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发表时间：
2011-01-24
期刊：
影响因子：
3.7
通讯作者：
Assaraf YG
中科院分区：
文献类型：
--
作者：
Goler-Baron V;Assaraf YG
多药耐药(MDR)是肿瘤化疗根治的主要障碍。ATP结合盒转运体ABCG2、ABCB1和ABCC2对多种结构和功能不同的化疗药物形成独特的防御网络，从而导致MDR。因此，破译MDR的新机制及其克服是癌症研究的主要目标。最近，我们发现ABCG2在乳腺癌细胞的新型细胞外小泡(EVS)膜上的过度表达导致米托蒽醌耐药，这是由于它在EVS中的显著隔离。然而，对EVS的结构、生物发生及其浓缩多种抗肿瘤药物的能力知之甚少。为此，我们在这里发现EVS是胆小管的结构和功能同源物，是顶端定位的封闭结构，由基于肌动蛋白的细胞骨架加强，并通过紧密连接蛋白occludin和ZO-1与细胞外环境隔绝。除ABCG2外，ABCB1和ABCC2也选择性地靶向于EVS的膜。此外，Ezrin-Radioxin-Moesin蛋白复合体选择性地定位于EVS膜的边缘，表明MDR泵与肌动蛋白细胞骨架的连接起着关键作用。对EVS浓缩和隔离不同抗肿瘤药物的能力也进行了探索。利用抗癌药物的内源性荧光，我们发现形成EVS的乳腺癌细胞通过有效的囊内药物浓度而对拓扑替康、咪唑并吖啶酮和甲氨蝶呤表现出高水平的耐药性，从而将它们隔离在细胞靶点之外。因此，我们确定了一种新的抗癌药物区隔和耐药模式，在这种模式下，多种化疗药物从细胞质中主动泵出，并通过针对EVS膜的MDR转运体网络在EVS的管腔内高度集中。我们提出了一个复合模型，用于研究癌细胞中富含多药耐药泵的EVS的结构和功能，以及它们产生多重抗癌耐药性的能力。
Multidrug resistance (MDR) is a major impediment to curative cancer chemotherapy. The ATP-Binding Cassette transporters ABCG2, ABCB1 and ABCC2 form a unique defense network against multiple structurally and functionally distinct chemotherapeutics, thereby resulting in MDR. Thus, deciphering novel mechanisms of MDR and their overcoming is a major goal of cancer research. Recently we have shown that overexpression of ABCG2 in the membrane of novel extracellular vesicles (EVs) in breast cancer cells results in mitoxantrone resistance due to its dramatic sequestration in EVs. However, nothing is known about EVs structure, biogenesis and their ability to concentrate multiple antitumor agents. To this end, we here found that EVs are structural and functional homologues of bile canaliculi, are apically localized, sealed structures reinforced by an actin-based cytoskeleton and secluded from the extracellular milieu by the tight junction proteins occludin and ZO-1. Apart from ABCG2, ABCB1 and ABCC2 were also selectively targeted to the membrane of EVs. Moreover, Ezrin-Radixin-Moesin protein complex selectively localized to the border of the EVs membrane, suggesting a key role for the tethering of MDR pumps to the actin cytoskeleton. The ability of EVs to concentrate and sequester different antitumor drugs was also explored. Taking advantage of the endogenous fluorescence of anticancer drugs, we found that EVs-forming breast cancer cells display high level resistance to topotecan, imidazoacridinones and methotrexate via efficient intravesicular drug concentration hence sequestering them away from their cellular targets. Thus, we identified a new modality of anticancer drug compartmentalization and resistance in which multiple chemotherapeutics are actively pumped from the cytoplasm and highly concentrated within the lumen of EVs via a network of MDR transporters differentially targeted to the EVs membrane. We propose a composite model for the structure and function of MDR pump-rich EVs in cancer cells and their ability to confer multiple anticancer drug resistance.
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