The Hsp90 inhibitor SNX-2112 induces apoptosis of human hepatocellular carcinoma cells: The role of ER stress
The Hsp90 inhibitor SNX-2112 induces apoptosis of human hepatocellular carcinoma cells: The role of ER stress
复制标题
Hsp90 抑制剂 SNX-2112 诱导人肝细胞癌细胞凋亡：ER 应激的作用。
DOI：
10.1016/j.bbrc.2014.02.081
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发表时间：
2014-03-28
影响因子：
3.1
通讯作者：
Wang, Yifei
中科院分区：
文献类型：
--
作者：
Wang, Xiao;Wang, Shaoxiang;Wang, Yifei
热休克蛋白90（Hsp 90）已被预测参与肝细胞癌（HCC）的治疗，然而，其作用机制仍然是难以捉摸的。SNX-2112是一种具有广泛抗肿瘤活性的Hsp 90抑制剂。在这里，我们的目的是确定的作用，内质网（ER）应激SNX 2112诱导的肝癌细胞凋亡。通常，三个HCC细胞（即，HepG 2、Huh 7和SK-Hepl）。通过CCK-8测定法测定细胞活力。采用流式细胞仪、激光扫描共聚焦显微镜（LSM）和Western blotting分析细胞凋亡情况。还在小鼠异种移植模型中评价了SNX-2112的疗效和作用机制。我们发现SNX-2112对细胞生长的抑制作用比经典的Hsp 90抑制剂17-AAG更强。SNX-2112处理导致caspase依赖性凋亡。有趣的是，SNX-2112降低了ER伴侣蛋白钙连接蛋白和免疫球蛋白结合蛋白（BiP）的表达水平。它还在体外和/或体内抑制所有三种ER应激传感器，即肌醇需要基因1（IRE 1）、PKR样ER ldnase（PERK）和激活转录因子6（ATF-6）。然而，ER应激诱导剂衣霉素强烈增强SNX-2112诱导的细胞凋亡，而IRE 1敲低则没有。总之，我们首次指出了SNX-2112在HCC细胞中可能的凋亡途径，提高了ER应激的诱导可能有利于SNX-2112诱导的凋亡的可能性。(c)2014爱思唯尔公司All rights reserved.
Heat shock protein 90 (Hsp90) has been predicted to be involved in hepatocellular carcinoma (HCC) therapy; however, the mechanisms of action remain elusive. SNX-2112 is an Hsp90 inhibitor showing broad antitumor activity. Here we aim to determine the role of the endoplasmic reticulum (ER) stress in SNX2112-induced apoptosis in HCC cells. In general, three HCC cells (i.e., HepG2, Huh7, and SK-Hepl) were used in our experiments. The cell viability was determined by the CCK-8 assay. The apoptosis was analyzed using flow cytometry, laser scanning confocal microscopy (LSM) and Western blotting. The efficacy and mechanisms of action of SNX-2112 were also evaluated in a mouse xenograft model. We found that SNX-2112 showed stronger inhibition on cell growth than 17-AAG, a classical Hsp90 inhibitor. SNX-2112 treatment led to the caspase-dependent apoptosis. Interestingly, SNX-2112 decreased the expression levels of the ER chaperone proteins calnexin and immunoglobulin binding protein (BiP). It also inhibited all three ER stress sensors, namely, inositol-requiring gene 1 (IRE1), PKR-like ER ldnase (PERK), and activating transcription factor 6 (ATF-6) in vitro and/or in vivo. However, the ER stress inducer tunicamycin strongly enhanced SNX-2112-induced apoptosis, whereas the IRE1 knockdown did not. Taken together, we for the first time indicated the possible apoptotic pathways of SNX-2112 in HCC cells, raising the possibility that the induction of ER stress might be favorable for SNX-2112-induced apoptosis. (c) 2014 Elsevier Inc. All rights reserved.