VCP inhibitors induce endoplasmic reticulum stress, cause cell cycle arrest, trigger caspase-mediated cell death and synergistically kill ovarian cancer cells in combination with Salubrinal
VCP inhibitors induce endoplasmic reticulum stress, cause cell cycle arrest, trigger caspase-mediated cell death and synergistically kill ovarian cancer cells in combination with Salubrinal
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DOI：
10.1016/j.molonc.2016.09.005
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发表时间：
2016-12-01
影响因子：
6.6
通讯作者：
Chien, Jeremy
中科院分区：
文献类型：
--
作者：
Bastola, Prabhakar;Neums, Lisa;Chien, Jeremy
Valosin-containing protein（VCP）又称p97，是AAA-ATP酶蛋白家族的成员，与内质网相关降解（ERAD）、高尔基体膜重组、自噬、DNA修复、细胞分裂等多种细胞功能密切相关。最近的研究表明VCP和泛素蛋白酶体系统（UPS）是卵巢癌的合成致死靶点。在这里，我们描述了VCP抑制剂在卵巢癌中的临床前活性。从我们的研究结果表明，喹唑啉为基础的VCP抑制剂启动G1期细胞周期阻滞，衰减帽依赖性翻译和诱导程序性细胞死亡，通过内在和外在的凋亡模式。机制研究指出未解决的未折叠蛋白反应（UPR）是VCP抑制剂导致细胞毒性的机制。这些结果支持了一个新兴的概念，即UPR和内质网（ER）应激途径可能是卵巢癌的脆弱性来源。由于长时间的ER应激可能导致CHOP介导的细胞死亡，我们测试了VCP抑制剂与增强CHOP表达的化合物协同作用的假设。在这里，我们发现VCP抑制剂与Salubrinal（eIF 2 α去磷酸化的抑制剂）通过增强卵巢癌细胞系中CHOP的表达而协同作用。我们的研究结果提供了一个概念验证，即VCP抑制剂可以作为单一药物使用，并且可以与增强CHOP表达的化合物协同作用，以诱导卵巢癌细胞的细胞死亡。(C)2016年欧洲生物化学学会联合会。Elsevier B. V.出版，保留所有权利。
Valosin-containing protein (VCP) or p97, a member of AAA-ATPase protein family, has been associated with various cellular functions including endoplasmic reticulum-associated degradation (ERAD), Golgi membrane reassembly, autophagy, DNA repair, and cell division. Recent studies identified VCP and ubiquitin proteasome system (UPS) as synthetic lethal targets in ovarian cancer. Here, we describe the preclinical activity of VCP inhibitors in ovarian cancer. Results from our studies suggest that quinazoline-based VCP inhibitors initiate G1 cell cycle arrest, attenuate cap-dependent translation and induce programmed cell death via the intrinsic and the extrinsic modes of apoptosis. Mechanistic studies point to the unresolved unfolded protein response (UPR) as a mechanism by which VCP inhibitors contribute to cytotoxicity. These results support an emerging concept that UPR and endoplasmic reticulum (ER) stress pathways may be targeted in ovarian cancer as a source of vulnerability. Since prolonged ER stress may result in CHOP-mediated cell death, we tested the hypothesis that VCP inhibitors act synergistically with compounds that enhance CHOP expression. Here, we show that VCP inhibitors act synergistically with Salubrinal, an inhibitor of eIF2 alpha dephosphorylation, by enhancing CHOP expression in ovarian cancer cell lines. Our results provide a proof-of-concept that VCP inhibitors can be used as a single agent and can be synergized with compounds that enhance CHOP expression to induce cell death in ovarian cancer cells. (C) 2016 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.