Mitochondria chaperone GRP75 moonlighting as a cell cycle controller to derail endocytosis provides an opportunity for nanomicrosphere intracellular delivery.
Mitochondria chaperone GRP75 moonlighting as a cell cycle controller to derail endocytosis provides an opportunity for nanomicrosphere intracellular delivery.
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线粒体伴侣 GRP75 兼职作为细胞周期控制器来破坏内吞作用，为纳米微球细胞内递送提供了机会
DOI：
10.18632/oncotarget.17234
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发表时间：
2017-08-29
期刊：
影响因子：
--
通讯作者：
Zhang S
中科院分区：
文献类型：
--
作者：
Gao Z;Niu X;Zhang Q;Chen H;Gao A;Qi S;Xiang R;Belting M;Zhang S
了解癌细胞在细胞周期中如何调节内吞作用可能会引导我们利用这一事件。虽然某些内吞途径在有丝分裂过程中被减弱，但细胞周期中内吞的转变和调控尚未得到很好的阐明。葡萄糖调节蛋白（GRP）作为蛋白质折叠分子伴侣的传统概念被更新的发现，易位GRP承担兼职功能，修改免疫反应，调节病毒释放，并控制细胞内运输。在这项研究中，GRP 75，线粒体基质伴侣，被发现在有丝分裂癌细胞中高度表达。利用同步化细胞模型和GRP 75基因敲低和异位过表达策略，我们发现：（1）在细胞周期M期，网格蛋白介导的内吞作用（CME）受到抑制，而网格蛋白非依赖性内吞作用（CIE）没有变化甚至上调;（2）GRP 75抑制CME，但促进M期的CIE，这主要是由于它在癌细胞线粒体中的高表达;（3）GRP 75的小分子抑制剂MKT-077靶向增强了细胞周期G1期特权的CME，这为尺寸为40 nm至100 nm的纳米微球的细胞内递送提供了机会。总之，我们的研究结果表明，GRP 75在癌细胞中作为细胞周期控制器和内吞调节剂，因此有可能作为纳米颗粒药物递送到休眠癌细胞中的新型干扰靶点。
Understanding how cancer cells regulate endocytosis during the cell cycle could lead us to capitalize this event pharmacologically. Although certain endocytosis pathways are attenuated during mitosis, the endocytosis shift and regulation during the cell cycle have not been well clarified. The conventional concept of glucose-regulated proteins (GRPs) as protein folding chaperones was updated by discoveries that translocated GRPs assume moonlighting functions that modify the immune response, regulate viral release, and control intracellular trafficking. In this study, GRP75, a mitochondria matrix chaperone, was discovered to be highly expressed in mitotic cancer cells. Using synchronized cell models and the GRP75 gene knockdown and ectopic overexpression strategy, we showed that: (1) clathrin-mediated endocytosis (CME) was inhibited whereas clathrin-independent endocytosis (CIE) was unchanged or even up-regulated in the cell cycle M-phase; (2) GRP75 inhibited CME but promoted CIE in the M-phase, which is largely due to its high expression in cancer cell mitochondria; (3) GRP75 targeting by its small molecular inhibitor MKT-077 enhanced cell cycle G1 phase-privileged CME, which provides an opportunity for intracellular delivery of nanomicrospheres sized from 40 nm to 100 nm. Together, our results revealed that GRP75 moonlights as a cell cycle controller and endocytosis regulator in cancer cells, and thus has potential as a novel interference target for nanoparticle drugs delivery into dormant cancer cells.
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