Emodin potentiates the antiproliferative effect of interferon α/β by activation of JAK/STAT pathway signaling through inhibition of the 26S proteasome.
Emodin potentiates the antiproliferative effect of interferon α/β by activation of JAK/STAT pathway signaling through inhibition of the 26S proteasome.
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DOI：
10.18632/oncotarget.6616
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发表时间：
2016-01-26
期刊：
影响因子：
--
通讯作者：
Wang F
中科院分区：
文献类型：
--
作者：
He Y;Huang J;Wang P;Shen X;Li S;Yang L;Liu W;Suksamrarn A;Zhang G;Wang F
26 S蛋白酶体是I型干扰素（IFN-α/β）信号传导的负调节剂。通过小分子抑制26 S蛋白酶体可能是增强I型IFN的功效并减少其副作用的新策略。利用细胞筛选法筛选新的26 S蛋白酶体抑制剂，我们发现大黄素，一种天然蒽醌，是一种有效的人26 S蛋白酶体抑制剂。大黄素优选地抑制人26 S蛋白酶体的半胱天冬酶样和胰凝乳蛋白酶样活性，并增加细胞中内源性蛋白质的泛素化。计算模型表明大黄素在26 S蛋白酶体的β1、β2和β5亚基的活性口袋中表现出有利于亲核攻击的取向/构象。大黄素增加IFN-α刺激的STAT 1磷酸化水平，降低STAT 3磷酸化水平，增加内源性基因表达。大黄素抑制IFN-α刺激的I型干扰素受体1（IFNAR 1）的泛素化和降解。大黄素还能敏化IFN-α对HeLa宫颈癌细胞的抗增殖作用，并抑制Huh 7肝癌荷瘤小鼠的肿瘤生长。这些结果表明，大黄素通过抑制26 S蛋白酶体刺激的IFNAR 1降解激活JAK/STAT信号通路增强IFN-α的抗增殖作用。因此，大黄素作为增强IFN-α/β疗效的新手段值得进一步研究。
The 26S proteasome is a negative regulator of type I interferon (IFN-α/β) signaling. Inhibition of the 26S proteasome by small molecules may be a new strategy to enhance the efficacy of type I IFNs and reduce their side effects. Using cell-based screening assay for new 26S proteasome inhibitors, we found that emodin, a natural anthraquinone, was a potent inhibitor of the human 26S proteasome. Emodin preferably inhibited the caspase-like and chymotrypsin-like activities of the human 26S proteasome and increased the ubiquitination of endogenous proteins in cells. Computational modeling showed that emodin exhibited an orientation/conformation favorable to nucleophilic attack in the active pocket of the β1, β2, and β5 subunits of the 26S proteasome. Emodin increased phosphorylation of STAT1, decreased phosphorylation of STAT3 and increased endogenous gene expression stimulated by IFN-α. Emodin inhibited IFN-α-stimulated ubiquitination and degradation of type I interferon receptor 1 (IFNAR1). Emodin also sensitized the antiproliferative effect of IFN-α in HeLa cervical carcinoma cells and reduced tumor growth in Huh7 hepatocellular carcinoma-bearing mice. These results suggest that emodin potentiates the antiproliferative effect of IFN-α by activation of JAK/STAT pathway signaling through inhibition of 26S proteasome-stimulated IFNAR1 degradation. Therefore, emodin warrants further investigation as a new means to enhance the efficacy of IFN-α/β.
影响因子：
1.9
作者：
Vetrivel U;Pilla K
通讯作者：
Pilla K