Furin-instructed molecular self-assembly actuates endoplasmic reticulum stress-mediated apoptosis for cancer therapy
Furin-instructed molecular self-assembly actuates endoplasmic reticulum stress-mediated apoptosis for cancer therapy
复制标题
弗林蛋白酶指导的分子自组装激活内质网应激介导的细胞凋亡用于癌症治疗
DOI：
10.1039/d0nr00151a
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发表时间：
2020-06-14
期刊：
影响因子：
6.7
通讯作者：
Ou, Caiwen
中科院分区：
文献类型：
--
作者：
Fu, Chenxing;Zhan, Jie;Ou, Caiwen
蛋白质质量控制和蛋白质稳态对于维持细胞存活至关重要，因为一旦蛋白质质量控制和蛋白质稳态紊乱，它们将触发内质网（ER）应激，甚至引发细胞凋亡。严重的内质网应激介导的细胞凋亡是神经退行性疾病的原因，有望成为肿瘤治疗的新靶点。在本研究中，我们设计了一个小分子1-Nap-furin指导的分子自组装体，在体外和体内选择性地抑制MDA-MB-468细胞的生长。透射电镜（TEM）和高效液相色谱（HPLC）示踪分析结果表明，1-Napis在弗林蛋白酶的诱导下发生自组装，将1-Naps纳米颗粒转变为1-Naps纳米纤维。荧光成像和Western-blot分析结果表明，1-Nap-furin诱导的自组装而不是其与ER靶向的相互作用是ER应激和细胞凋亡激活所必需的。弗林蛋白酶指导的1-Napis的自组装与ER（1-Nap的靶向位置）和trans-Golgi网络（弗林蛋白酶的位置）相关;这启发我们合理地相信，通过分子自组装阻断分泌途径中的ER到高尔基体的交通可能是控制细胞命运的内在动机。本工作为通过分子自组装靶向干扰细胞蛋白质稳态开发肿瘤治疗药物提供了新的途径。
Protein quality control and proteostasis are essential to maintain cell survival as once disordered, they will trigger endoplasmic reticulum (ER) stress and even initiate apoptosis. Severe ER stress-mediated apoptosis is the cause of neurodegenerative diseases and expected to be a new target for cancer therapy. In this study, we designed a small molecule of1-Napto execute furin-instructed molecular self-assembly for selectively inhibiting the growth of MDA-MB-468 cellsin vitroandin vivo. According to the results of transmission electron microscopy (TEM) and HPLC tracing analysis,1-Napis capable of self-assembling upon furin-instructed cleavage that transforms1-Napnanoparticles to1-Napnanofibers. Fluorescence imaging and Western-blot analysis results indicate that the furin-instructed self-assembly of1-Naprather than its ER-targeting interaction is indispensable for the ER stress and activation of apoptosis. The furin-instructed self-assembly of1-Napis associated with both the ER (1-Nap's targeting location) and the trans-Golgi network (furin's location); this inspired us to reasonably believe that the blocking of ER-to-Golgi traffic in the secretory pathway by molecular self-assembly may be the intrinsic motivation for controlling cell fate. This work provides a new way for the targeted disturbance of the proteostasis of cells through molecular self-assembly for developing cancer therapeutics.