Epidermal growth factor-nanoparticle conjugates change the activity from anti-apoptotic to pro-apoptotic at membrane rafts
Epidermal growth factor-nanoparticle conjugates change the activity from anti-apoptotic to pro-apoptotic at membrane rafts
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DOI：
10.1016/j.actbio.2019.02.026
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发表时间：
2019-04-01
影响因子：
9.7
通讯作者：
Nakanishi, Jun
中科院分区：
文献类型：
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作者：
Yamamoto, Shota;Iwamaru, Yoshifumi;Nakanishi, Jun
已知增殖表皮生长因子（EGF）通过迄今未知的机制在与金纳米颗粒（GNP）缀合后获得矛盾的凋亡活性。在这里，我们确定了膜筏的EGF-GNP通过以下细胞内信号的剧烈活动切换中的重要作用。(1)与可溶性EGF刺激后激活的EGF受体的快速扩散相反，受体在结合EGF-GNP时被限制在膜筏内。(2)这种最初的受体限制将其内吞过程从正常的网格蛋白介导的内吞转换为小窝蛋白介导的内吞，改变了必需的下游激酶的磷酸化动力学，即，细胞外信号调节激酶和AKT。重要的是，β-环糊精对膜筏的破坏逆转了这种运输和信号传导，使EGF-GNP恢复到失去的抗凋亡特性。这些结果揭示了GNP介导的信号浓缩在膜筏上赋予EGF-纳米颗粒conjugated.Statement的独特的凋亡活性的重要性表皮生长因子（EGF）是一种小的分泌蛋白，诱导细胞增殖后结合其受体存在于细胞质膜上。在纳米生物学领域的蛋白质的一个有趣的特点是，其收购的凋亡诱导（细胞自杀）的活动，而不是通过迄今为止未知的机制共轭金纳米粒子增殖之一。在这里，我们确定了膜筏，富含胆固醇的质膜纳米结构域，通过改变受体运输和下游信号转导途径参与细胞凋亡过程。此外，脂筏的破坏恢复了失去抗凋亡活性的EGF-纳米颗粒缀合物。这些发现突出了EGF-纳米颗粒缀合物在癌症治疗中的潜在应用，因为EGF受体在癌细胞中高度表达。(C)2019 Acta Materialia Inc.由爱思唯尔有限公司出版。保留所有权利。
The proliferation epidermal growth factor (EGF) is known to acquire contradictory apoptotic activities upon conjugation with gold nanoparticles (GNPs) through hitherto unknown mechanisms. Here, we identified an essential role of membrane rafts in the drastic activity switching of EGF-GNPs through the following intracellular signaling. (1) In contrast to the rapid diffusion of activated EGF receptor after the soluble EGF stimulation, the receptor is confined within membrane rafts upon binding to the EGF-GNPs. (2) This initial receptor confinements switch its endocytosis process from normal clathrin-mediated endocytosis to caveolin-mediated one, changing the phosphorylation dynamics of essential downstream kinases, i.e., extracellular signal-regulated kinase and AKT. Importantly, the destruction of membrane rafts by beta-cyclodextrin reversed this trafficking and signaling, restoring EGF-GNPs to lost anti-apoptotic property. These results reveal the importance of GNP-mediated signal condensation at membrane rafts in conferring the unique apoptotic activity on EGF-nanoparticle conjugates.Statement of significanceEpidermal growth factor (EGF) is a small secretory protein that induces cell proliferation upon binding to its receptor existed on cellular plasma membranes. One interesting feature of the protein in the nanobiology field is, its acquisition of apoptosis-inducing (cellular suicide) activity rather than proliferative one upon conjugation to gold nanoparticles through hitherto unknown mechanisms. Here, we identified the involvement of membrane rafts, plasma membrane nanodomains enriched with cholesterol, in the apoptosis processes by changing the receptor trafficking and downstream signal transduction pathways. Moreover, the destruction of lipid rafts restored the EGF-nanoparticle conjugates with lost antiapoptotic activity. These finding highlight potential applications of EGF-nanoparticle conjugates to cancer therapy, as the EGF receptor are highly expressed in cancer cells. (C) 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.