PDF(Pubmed)
Abstract：
Extracellular vesicles (EVs) are important mediators of intercellular communication in the tumour microenvironment. Many studies suggest that cancer cells release higher amounts of EVs exposing phosphatidylserine (PS) at the surface. There are lots of interconnections between EVs biogenesis and autophagy machinery. Modulation of autophagy can probably affect not only the quantity of EVs but also their content, which can deeply influence the resulting pro-tumourigenic or anticancer effect of autophagy modulators. In this study, we found that autophagy modulators autophinib, CPD18, EACC, bafilomycin A1 (BAFA1), 3-hydroxychloroquine (HCQ), rapamycin, NVP-BEZ235, Torin1, and starvation significantly alter the composition of the protein content of phosphatidylserine-positive EVs (PS-EVs) produced by cancer cells. The greatest impact had HCQ, BAFA1, CPD18, and starvation. The most abundant proteins in PS-EVs were proteins typical for extracellular exosomes, cytosol, cytoplasm, and cell surface involved in cell adhesion and angiogenesis. PS-EVs protein content involved mitochondrial proteins and signalling molecules such as SQSTM1 and TGFβ1 pro-protein. Interestingly, PS-EVs contained no commonly determined cytokines, such as IL-6, IL-8, GRO-α, MCP-1, RANTES, and GM-CSF, which indicates that secretion of these cytokines is not predominantly mediated through PS-EVs. Nevertheless, the altered protein content of PS-EVs can still participate in the modulation of the fibroblast metabolism and phenotype as p21 was accumulated in fibroblasts influenced by EVs derived from CPD18-treated FaDu cells. The altered protein content of PS-EVs (data are available via ProteomeXchange with identifier PXD037164) also provides information about the cellular compartments and processes that are affected by the applied autophagy modulators. Video Abstract.
摘要：
细胞外囊泡（EV）是肿瘤微环境中细胞间通讯的重要介质。许多研究表明，癌细胞在表面释放更大量的暴露磷脂酰丝氨酸（PS）的EV。电动汽车的生物发生和自噬机制之间存在许多相互联系。自噬的调节可能不仅会影响电动汽车的数量，还会影响其含量，这可以深深地影响自噬调节剂产生的促肿瘤或抗癌作用。在这项研究中,我们发现自噬调节剂autophinib，CPD18,EACC,巴弗洛霉素A1（BAFA1），3-羟基氯喹（HCQ），雷帕霉素,NVP-BEZ235，Torin1和饥饿显着改变了由癌细胞产生的磷脂酰丝氨酸阳性EV（PS-EV）的蛋白质含量的组成。最大的影响是HCQ，BAFA1、CPD18和饥饿。PS-EV中最丰富的蛋白质是细胞外泌体的典型蛋白质，胞质溶胶,细胞质，和细胞表面参与细胞粘附和血管生成。PS-EV蛋白含量涉及线粒体蛋白和信号分子，例如SQSTM1和TGFβ1前蛋白。有趣的是,PS-EV不含通常确定的细胞因子，如IL-6，IL-8，GRO-α，MCP-1RANTES,和GM-CSF,这表明这些细胞因子的分泌不是主要通过PS-EV介导的。然而，PS-EV的蛋白质含量改变仍可参与成纤维细胞代谢和表型的调节,因为p21在源自CPD18处理的FaDu细胞的EV影响下在成纤维细胞中积累.PS-EV的改变的蛋白质含量（数据可通过具有标识符PXD037164的ProteomeXchange获得）还提供有关受应用的自噬调节剂影响的细胞区室和过程的信息。视频摘要。
