Hsp90抑制剂对未折叠蛋白反应作用的研究进展  

Progresses on Hsp90 Inhibitor Targeting Unfolded Protein Response

作　　者：申跃武[1] 韩钢杰 马亚洪 蔡晓明[1] 刘云[1] 母波[1] 

机构地区：[1]川北医学院基础医学实验教学中心,中国四川南充637000 [2]川北医学院临床医学系,中国四川南充637000

出　　处：《生命科学研究》2017年第1期64-68,共5页Life Science Research

基　　金：国家自然科学基金资助项目(81101733);四川省教育厅项目(13ZA0240);四川省卫生厅项目(130288);川北医学院科研项目(CBYA-Z903)

摘　　要：肿瘤细胞因癌基因突变、缺氧及营养受限而高度依赖未折叠蛋白反应(unfolded protein response,UPR)。细胞通过内质网(endoplasmic reticulum,ER)膜上3个跨膜蛋白感知未折叠蛋白信号,引起未折叠蛋白反应,动态调控内质网折叠能力,一方面通过暂时减缓翻译和加快蛋白质流出减少ER蛋白质折叠负担,另一方面通过转录因子提高伴侣分子合成,增加ER折叠能力。未折叠的蛋白质长时间积聚在ER会对细胞产生毒性,引起不能缓解的ER应激状态,启动细胞凋亡程序。热休克蛋白90(heat shock protein 90,Hsp90)是一种进化保守的伴侣分子,参与了300多种新生蛋白质的折叠与成熟,其中包括UPR重要信号IRE1α(inositol-requiring enzyme 1α)。Hsp90抑制剂导致细胞产生大量未折叠蛋白质,同时直接诱导IRE1α的降解,从而破坏UPR恢复蛋白质平衡的能力,诱导UPR相关凋亡。目前,Hsp90抑制剂可有效诱导分泌型肿瘤细胞如骨髓瘤以及RAS突变肿瘤UPR途径的凋亡。Due to oncogene mutation and stressful environments including hypoxia, nutritional stress and pH stress, tumor cells are often subjected to endoplasmic reticulum （ER） protein folding stress. Cellular adaptation to ER stress is achieved by the activation of unfolded protein response （UPR）. There are three key transmem- brahe proteins on the ER membrane to sense and process unfolded protein signals. The outcome of UPR ac- tivation involves transient attenuation of protein synthesis, increased capacity for protein trafficking through the ER, protein folding and transport, and increased protein degradation through ER-associated degradation （ERAD）. However, above a certain threshold, chronic UPR results in apoptosis. Heat shock protein 90 （Hsp90） is an evolutionarily conserved molecular chaperone, involving in stabilization and activation of over 300 client proteins. Hsp90 inhibitors disrupt folding and maturation of the client proteins, and cause degra- dation of inositol-requiring enzyme le- （IREle-）, the essential UPR signal. So far, the inhibitors could effectively elicit UPR-mediated apoptosis of secretory tumors like multiple mveloma and RAS-driven turnnvs

关 键 词：未折叠蛋白反应（UPR） 热休克蛋白90（Hsp90） HSP90抑制剂 肿瘤 细胞凋亡 内质网（ER） 

分 类 号：Q291[生物学—细胞生物学]