Targeting the AAA ATPase p97 as an Approach to Treat Cancer through Disruption of Protein Homeostasis.
Targeting the AAA ATPase p97 as an Approach to Treat Cancer through Disruption of Protein Homeostasis.
复制标题
靶向AAA ATPase P97作为通过蛋白质稳态的破坏来治疗癌症的方法。
DOI：
10.1016/j.ccell.2015.10.002
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发表时间：
2015-11-09
期刊：
影响因子：
50.3
通讯作者：
Rolfe M
中科院分区：
文献类型：
--
作者：
Anderson DJ;Le Moigne R;Djakovic S;Kumar B;Rice J;Wong S;Wang J;Yao B;Valle E;Kiss von Soly S;Madriaga A;Soriano F;Menon MK;Wu ZY;Kampmann M;Chen Y;Weissman JS;Aftab BT;Yakes FM;Shawver L;Zhou HJ;Wustrow D;Rolfe M
p97 是一种具有多种细胞功能的 AAA-ATP 酶，其中之一是蛋白质稳态途径的关键调节。我们描述了 CB-5083 的表征，CB-5083 是一种有效的、选择性的、口服生物可利用的 p97 抑制剂。用 CB-5083 处理肿瘤细胞会导致多聚泛素化蛋白的积累、内质网相关降解 (ERAD) 底物的保留以及不可解决的蛋白毒性应激的产生，从而导致未折叠蛋白反应 (UPR) 的凋亡臂激活。在异种移植模型中，CB-5083 会调节关键的 p97 相关途径，诱导细胞凋亡，并在多种血液学和实体瘤模型中具有抗肿瘤活性。 CB-5083 活性的分子决定因素包括 ERAD 通路中基因的表达，为患者选择提供了潜在的策略。
p97 is a AAA-ATPase with multiple cellular functions, one of which is critical regulation of protein homeostasis pathways. We describe the characterization of CB-5083, a potent, selective and orally bioavailable inhibitor of p97. Treatment of tumor cells with CB-5083 leads to accumulation of poly-ubiquitinated proteins, retention of endoplasmic reticulum associated degradation (ERAD) substrates and generation of irresolvable proteotoxic stress leading to activation of the apoptotic arm of the unfolded protein response (UPR). In xenograft models, CB-5083 causes modulation of key p97-related pathways, induces apoptosis and has antitumor activity in a broad range of both hematological and solid tumor models. Molecular determinants of CB-5083 activity include expression of genes in the ERAD pathway providing a potential strategy for patient selection.