Celastrol induces apoptosis in hepatocellular carcinoma cells via targeting ER-stress/UPR.
Celastrol induces apoptosis in hepatocellular carcinoma cells via targeting ER-stress/UPR.
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DOI：
10.18632/oncotarget.21750
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发表时间：
2017-11-03
期刊：
影响因子：
--
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Ren B;Liu H;Gao H;Liu S;Zhang Z;Fribley AM;Callaghan MU;Xu Z;Zeng Q;Li Y
肝细胞癌（HCC）是全世界最严重和致命的疾病之一，有效治疗的选择有限。基于生物标志物的活性化合物靶向治疗可能为 HCC 新药的开发提供一些线索。内质网（ER）应激和未折叠蛋白反应（UPR）在细胞命运的调节中发挥着重要作用，并已成为抗癌药物开发的新信号靶点。雷公藤红素是一种中药三萜类化合物，据报道对多种癌症具有抗肿瘤作用。我们与其他几个研究小组最近报道，雷公藤红素在包括肝细胞癌在内的几种不同癌症中诱导 UPR。然而，肝癌中的 UPR 状态仍不清楚。内质网应激和自噬在雷公藤红醇反应中的作用也尚未阐明。我们的结果表明雷公藤红素可以引起 G2/M 期休息并抑制 HepG2 和 Bel7402 的增殖。暴露于雷公藤红素会通过内质网应激和 UPR 激活内在的细胞凋亡途径。在小鼠同系模型研究中，雷公藤红醇通过诱导 ER 应激和细胞凋亡来抑制 H22 肿瘤生长。我们的研究表明，雷公藤红素是一种通过靶向 ER 应激/UPR 来治疗 HCC 的潜在药物。
Hepatocellular carcinoma (HCC) is one of the most serious and deadly diseases worldwide with limited options for effective treatment. Biomarker-based active compound targeting therapy may shed some light on novel drugs for HCC. The endoplasmic reticulum (ER) stress and unfolded protein response (UPR) play important roles in the regulation of cell fate and have become novel signaling targets for the development of anticancer drugs. Celastrol, a triterpene from traditional Chinese medicine, has been reported to possess anti-tumor effects on various cancers. We, along with several other research groups, have recently reported that UPR was induced by celastrol in several different cancers, including hepatocellular carcinoma. However, UPR status in HCC still remains unclear. The role of ER stress and autophagy in response to celastrol also has yet to be elucidated. Our results demonstrated that celastrol could cause G2/M phase rest and inhibit proliferation in HepG2 and Bel7402. Exposure to celastrol resulted in the activation of the intrinsic apoptotic pathway, via ER stress and the UPR. In murine syngeneic model studies celastrol inhibited H22 tumor growth via the induction of ER stress and apoptosis. Our study suggests that celastrol is a potential drug for HCC therapy via targeting ER-stress/UPR.
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