Disruption of the unfolded protein response (UPR) by lead compound selectively suppresses cancer cell growth
Disruption of the unfolded protein response (UPR) by lead compound selectively suppresses cancer cell growth
复制标题
先导化合物破坏未折叠蛋白反应（UPR）可选择性抑制癌细胞生长
DOI：
10.1016/j.canlet.2015.02.029
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发表时间：
2015-05-01
期刊：
影响因子：
9.7
通讯作者：
Li, Jia
中科院分区：
文献类型：
--
作者：
Huang, Hejing;Liu, Huanan;Li, Jia
识别对癌细胞具有高选择性的化疗候选物是癌症治疗中的主要挑战。肿瘤微环境引起慢性内质网（ER）应激并激活未折叠蛋白反应（UPR）作为适应性反应。在这里，一种新型小分子化合物 17# 被发现是一种有效的泛 UPR 抑制剂。当癌细胞在 2-脱氧-D-葡萄糖 (2DG) 中培养时，它表现出良好的生长抑制选择，模拟体外葡萄糖剥夺状态。此外，单独使用17#可以轻度抑制HeLa肿瘤异种移植物的生长，并且当17#与2DG联合时观察到协同抗癌作用。机制研究表明，17#诱导的选择性抗癌作用高度依赖于UPR抑制，而过表达GRP78或XBP1s可以逆转17#诱导的生长抑制和细胞周期停滞，部分是通过延迟细胞周期调节因子cyclin B1的下调来实现的。此外，17#还提高了阿霉素或依托泊苷等抗癌药物的敏感性。我们的研究提供的证据表明，破坏 UPR 具有选择性治疗潜力，并可能增强药物敏感性。 (C) 2015 Elsevier Ireland Ltd. 保留所有权利。
Identifying chemotherapy candidates with high selectivity against cancer cells is a major challenge in cancer treatment. Tumor microenvironments cause chronic endoplasmic reticulum (ER) stress and activate the unfolded protein response (UPR) as an adaptive response. Here, one novel small-molecule compound, 17#, was discovered as a potent pan-UPR inhibitor. It exhibited good selection for growth inhibition when cancer cells were cultured in 2-deoxy-D-glucose (2DG), mimicking an in vitro glucose-deprived status. Additionally, 17# alone could mildly suppress the growth of HeLa tumor xenografts, and a synergistic anti-cancer effect was observed when 17# was combined with 2DG. A mechanistic study showed that 17#-induced selective anti-cancer effects were highly dependent on UPR inhibition, and overexpressing GRP78 or XBP1s reversed the 17#-induced growth inhibition and cell cycle arrest, partially by delaying the downregulation of the cell cycle regulator cyclin B1. Furthermore, 17# improved the sensitivity of anti-cancer drugs such as doxorubicin or etoposide. Our study presents evidence that disrupting the UPR has selective therapeutic potential and may enhance drug sensitivity. (C) 2015 Elsevier Ireland Ltd. All rights reserved.