Dietary quercetin potentiates the antiproliferative effect of interferon-α in hepatocellular carcinoma cells through activation of JAK/STAT pathway signaling by inhibition of SHP2 phosphatase.
Dietary quercetin potentiates the antiproliferative effect of interferon-α in hepatocellular carcinoma cells through activation of JAK/STAT pathway signaling by inhibition of SHP2 phosphatase.
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膳食槲皮素通过抑制 SHP2 磷酸酶激活 JAK/STAT 信号通路，增强干扰素 α 在肝细胞癌细胞中的抗增殖作用
DOI：
10.18632/oncotarget.22556
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发表时间：
2017-12-26
期刊：
影响因子：
--
通讯作者：
Wang F
中科院分区：
文献类型：
--
作者：
Igbe I;Shen XF;Jiao W;Qiang Z;Deng T;Li S;Liu WL;Liu HW;Zhang GL;Wang F
I型干扰素（IFN-α/β）具有广泛而有效的免疫调节和抗增殖活性，其活性受含Src同源结构域2的酪氨酸磷酸酶-2（SHP-2）负调控。小分子抑制SHP 2可能是增强I型IFN疗效的新策略。使用体外筛选试验的新的抑制剂的SHP 2磷酸酶，我们发现，槲皮素是一种有效的抑制剂的SHP 2。计算模型表明，槲皮素在SHP 2的磷酸酶结构域中表现出有利于亲核攻击的取向。槲皮素可增强信号转导和转录激活蛋白1（STAT 1）的磷酸化，促进内源性IFN-α调控基因的表达。槲皮素还能增强IFN-α对肝癌细胞HepG 2和Huh 7的抗增殖作用。SHP 2的过表达减弱了槲皮素对IFN-α诱导的STAT 1磷酸化和抗增殖效应的影响，而抑制SHP 2则增强了槲皮素对IFN-α诱导的STAT 1磷酸化和抗增殖效应的影响。结果表明，槲皮素通过抑制SHP 2激活JAK/STAT信号通路，增强IFN-α对肿瘤细胞增殖的抑制作用。槲皮素作为增强IFN-α/β疗效的新治疗方法值得进一步研究。
Type I interferons (IFN-α/β) have broad and potent immunoregulatory and antiproliferative activities, which are negatively regulated by Src homology domain 2 containing tyrosine phosphatase-2 (SHP-2). Inhibition of SHP2 by small molecules may be a new strategy to enhance the effcacy of type I IFNs. Using an in vitro screening assay for new inhibitors of SHP2 phosphatase, we found that quercetin was a potent inhibitor of SHP2. Computational modeling showed that quercetin exhibited an orientation favorable to nucleophilic attack in the phosphatase domain of SHP2. Quercetin enhanced the phosphorylation of signal transducer and activator of transcription proteins 1 (STAT1) and promoted endogenous IFN-α-regulated gene expression. Furthermore, quercetin also sensitized the antiproliferative effect of IFN-α on hepatocellular carcinoma HepG2 and Huh7 cells. The overexpression of SHP2 attenuated the effect of quercetin on IFN-α-stimulated STAT1 phosphorylation and antiproliferative effect, whereas the inhibition of SHP2 promoted the effect of quercetin on IFN-α-induced STAT1 phosphorylation and antiproliferative effect. The results suggested that quercetin potentiated the inhibitory effect of IFN-α on cancer cell proliferation through activation of JAK/STAT pathway signaling by inhibiting SHP2. Quercetin warrants further investigation as a novel therapeutic method to enhance the efficacy of IFN-α/β.
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影响因子：
4.6
作者：
Konishi, Hideyuki;Okamoto, Koichi;Ohmori, Yusuke;Yoshino, Hitoshi;Ohmori, Hiroshi;Ashihara, Motooki;Hirata, Yuichi;Ohta, Atsunori;Sakamoto, Hiroshi;Hada, Natsuko;Katsume, Asao;Kohara, Michinori;Morikawa, Kazumi;Tsukuda, Takuo;Shimma, Nobuo;Foster, Graham R.;Alazawi, William;Aoki, Yuko;Arisawa, Mikio;Sudoh, Masayuki
通讯作者：
Sudoh, Masayuki
影响因子：
--
作者：
He Y;Huang J;Wang P;Shen X;Li S;Yang L;Liu W;Suksamrarn A;Zhang G;Wang F
通讯作者：
Wang F
影响因子：
6.1
作者：
Häkkinen, SH;Kärenlampi, SO;Törrönen, AR
通讯作者：
Törrönen, AR
影响因子：
1.7
作者：
Lin, Yuan;Wang, Fei;Zhang, Guo-Lin
通讯作者：
Zhang, Guo-Lin
膳食芹菜素通过抑制 26S 蛋白酶体介导的干扰素受体降解，增强干扰素 α 对癌细胞活力的抑制作用
影响因子：
3.3
作者：
Li S;Yang LJ;Wang P;He YJ;Huang JM;Liu HW;Shen XF;Wang F
通讯作者：
Wang F