The inhibition of death receptor mediated apoptosis through lysosome stabilization following internalization of carboxyfullerene nanoparticles
The inhibition of death receptor mediated apoptosis through lysosome stabilization following internalization of carboxyfullerene nanoparticles
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羧基富勒烯纳米粒子内化后通过溶酶体稳定来抑制死亡受体介导的细胞凋亡
DOI：
10.1016/j.biomaterials.2011.02.008
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发表时间：
2011-06-01
期刊：
影响因子：
14
通讯作者：
Chen, Chunying
中科院分区：
文献类型：
--
作者：
Li, Wei;Zhao, Lina;Chen, Chunying
细胞通过两种主要途径进行凋亡，即外在途径（死亡受体途径）和内在途径（线粒体途径）。众所周知，水溶性富勒烯衍生物纳米材料是有效的抗氧化剂，有助于防止线粒体活性氧（ROS）的过度产生。然而，它们通过死亡受体途径与细胞的相互作用是直接的还是间接的仍然知之甚少。在这里，我们发现富勒烯的双加成丙二酸衍生物C-60（C（COOH）（2））（2）通过稳定溶酶体抑制肿瘤坏死因子α引发的细胞凋亡。本文提供的数据表明，这种水溶性富勒烯衍生物的纳米级聚集体被内吞到细胞中并在溶酶体中富集。在C-60（C（COOH）（2））（2）的内化过程中，Hsp 70的表达显著上调，通过抑制溶酶体膜的透化作用促进细胞存活。此外，溶酶体内的酸性环境对富勒烯纳米颗粒的尺寸分布具有显著但暂时的影响，并且可以将聚集的C-60（C（COOH）（2））（2）纳米颗粒分散成单个分子或更小的聚集体。这些单分子或更小的聚集体可以插入溶酶体膜中，进一步稳定它们并减少组织蛋白酶从溶酶体的释放，导致抑制肿瘤坏死因子诱导的细胞凋亡。因此，C-60（C（COOH）（2））（2）纳米颗粒可以通过上调Hsp 70的表达以及通过它们与溶酶体膜的相互作用稳定溶酶体膜来保护细胞。(C)2011爱思唯尔有限公司保留所有权利。
Cells undergo apoptosis through two major pathways, the extrinsic pathway (death receptor pathway) and the intrinsic pathway (the mitochondrial pathway). It is well known that nanomaterials of water-soluble fullerene derivatives are potent antioxidants and help to prevent the overproduction of mitochondrial reactive oxygen species (ROS). However, whether their interaction with cells via the death receptor pathway is direct or indirect remains poorly understood. Here, we show that a bis-adduct malonic acid derivative of fullerene, C-60(C(COOH)(2))(2), inhibits tumor necrosis factor alpha-initiated cellular apoptosis via stabilizing lysosomes. Data presented here demonstrate that nano-sized aggregates of this water-soluble fullerene derivative are endocytosed into cells and enriched in the lysosomes. During the internalization of C-60(C(COOH)(2))(2), the expression of Hsp 70 is significantly upregulated, promoting cell survival by inhibiting the permeabilization of lysosomal membranes. In addition, the acidic environment inside lysosomes has a marked but temporary effect on the size distribution of fullerenic nanoparticles, and may disperse the aggregated C-60(C(COOH)(2))(2) nanoparticles into single molecules or smaller aggregates. These single molecules or smaller aggregates may insert into the lysosomal membranes, further stabilizing them and decreasing the release of cathepsins from lysosomes, leading to the inhibition of tumor necrosis factor-induced apoptosis. C-60(C(COOH)(2))(2) nanoparticles can thus protect cells by stabilizing lysosomal membranes via both upregulated expression of Hsp 70 and by their interactions with lysosomal membranes. (C) 2011 Elsevier Ltd. All rights reserved.