Chaperone-Targeting Cytotoxin and Endoplasmic Reticulum Stress-Inducing Drug Synergize to Kill Cancer Cells
Chaperone-Targeting Cytotoxin and Endoplasmic Reticulum Stress-Inducing Drug Synergize to Kill Cancer Cells
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DOI：
10.1593/neo.09878
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发表时间：
2009-11-01
期刊：
影响因子：
4.8
通讯作者：
Backer, Marina V.
中科院分区：
文献类型：
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作者：
Backer, Joseph M.;Krivoshein, Arcadius V.;Backer, Marina V.
不同的生理和治疗侮辱会增加内质网(ER)中未折叠或错误折叠的蛋白质的数量，从而诱导未折叠蛋白质反应，这是一种进化上保守的保护机制，用于管理内质网应激。葡萄糖调节蛋白78/免疫球蛋白重链结合蛋白(GRP78/Bip)是一种内质网驻留蛋白，在内质网应激反应中发挥核心作用，也是一种新的细菌AB5毒素蛋白分解A亚单位(Suba)的唯一已知底物。在这里，我们报道了一种工程融合蛋白，表皮生长因子(EGF)-SuBA，结合EGF和SuBA，对生长和融合的表皮生长因子受体表达的癌细胞具有高度毒性，其细胞毒性是由GRP78/Bip非常迅速的切割所介导的。全身注射EGF-SuBA可显著抑制小鼠模型中人乳腺和前列腺癌的异种移植。此外，EGF-Suba显著增加癌细胞对内质网应激诱导药物thapsigargin的敏感性，反之亦然，展示了细胞毒素和内质网靶向药物作用中基于机制的协同作用的第一个例子。
Diverse physiological and therapeutic insults that increase the amount of unfolded or misfolded proteins in the endoplasmic reticulum (ER) induce the unfolded protein response, an evolutionarily conserved protective mechanism that manages ER stress. Glucose-regulated protein 78/immunoglobulin heavy-chain binding protein (GRP78/BiP) is an ER-resident protein that plays a central role in the ER stress response and is the only known substrate of the proteolytic A subunit (SubA) of a novel bacterial AB5 toxin. Here, we report that an engineered fusion protein, epidermal growth factor (EGF)-SubA, combining EGF and SubA, is highly toxic to growing and confluent epidermal growth factor receptor-expressing cancer cells, and its cytotoxicity is mediated by a remarkably rapid cleavage of GRP78/BiP. Systemic delivery of EGF-SubA results in a significant inhibition of human breast and prostate tumor xenografts in mouse models. Furthermore, EGF-SubA dramatically increases the sensitivity of cancer cells to the ER stress-inducing drug thapsigargin, and vice versa, demonstrating the first example of mechanism-based synergism in the action of a cytotoxin and an ER-targeting drug.