The Hydroxyquinoline Analogue YUM70 Inhibits GRP78 to Induce ER Stress-Mediated Apoptosis in Pancreatic Cancer.
The Hydroxyquinoline Analogue YUM70 Inhibits GRP78 to Induce ER Stress-Mediated Apoptosis in Pancreatic Cancer.
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DOI：
10.1158/0008-5472.can-20-1540
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发表时间：
2021-04-01
期刊：
影响因子：
11.2
通讯作者：
Neamati N
中科院分区：
文献类型：
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作者：
Samanta S;Yang S;Debnath B;Xue D;Kuang Y;Ramkumar K;Lee AS;Ljungman M;Neamati N
GRP 78（葡萄糖调节蛋白，78 kDa）是内质网（内质网）应激信号传导的关键调节因子。癌细胞是高度增殖的，并且对蛋白质合成和折叠有很高的需求，这导致对ER的显著压力。为了响应ER应激并维持细胞稳态，细胞激活未折叠蛋白反应（UPR），其促进存活或凋亡性死亡。癌细胞利用UPR来促进存活和生长。在这项研究中，我们描述了一系列新的羟基喹啉GRP 78抑制剂的发现。代表性类似物YUM 70在体外抑制胰腺癌细胞生长，并在胰腺癌异种移植模型中显示出体内功效，对正常组织没有毒性。YUM 70直接结合GRP 78并使其功能失活，导致ER应激介导的细胞凋亡。与BODIPY缀合的YUM 70类似物显示化合物与GRP 78在ER中的共定位。此外，合成YUM 70-PROTAC（PROteolysis Targeting Chimera）以迫使胰腺癌细胞中的GRP 78降解。YUM 70与拓扑替康和伏立诺他显示出强的协同细胞毒性。总之，我们的研究表明，YUM 70是一种新的ER应激诱导剂，作为胰腺癌的单一疗法或与拓扑异构酶和HDAC抑制剂组合具有临床前疗效。
GRP78 (Glucose-regulated protein, 78 kDa) is a key regulator of ER (endoplasmic reticulum) stress signaling. Cancer cells are highly proliferative and have high demand for protein synthesis and folding, which results in significant stress on the ER. To respond to ER stress and maintain cellular homeostasis, cells activate the unfolded protein response (UPR) that promotes either survival or apoptotic death. Cancer cells utilize the UPR to promote survival and growth. In this study, we describe the discovery of a series of novel hydroxyquinoline GRP78 inhibitors. A representative analog, YUM70, inhibited pancreatic cancer cell growth in vitro and showed in vivo efficacy in a pancreatic cancer xenograft model with no toxicity to normal tissues. YUM70 directly bound GRP78 and inactivated its function, resulting in ER stress-mediated apoptosis. A YUM70 analog conjugated with BODIPY show co-localization of the compound with GRP78 in the ER. Moreover, a YUM70-PROTAC (PROteolysis TArgeting Chimera) was synthesized to force degradation of GRP78 in pancreatic cancer cells. YUM70 showed a strong synergistic cytotoxicity with topotecan and vorinostat. Together, our study demonstrates that YUM70 is a novel inducer of ER stress with preclinical efficacy as a monotherapy or in combination with topoisomerase and HDAC inhibitors in pancreatic cancer.