6-Hydroxy-3-O-methyl-kaempferol 6-O-glucopyranoside potentiates the anti-proliferative effect of interferon alpha/beta by promoting activation of the JAK/STAT signaling by inhibiting SOCS3 in hepatocellular carcinoma cells
6-Hydroxy-3-O-methyl-kaempferol 6-O-glucopyranoside potentiates the anti-proliferative effect of interferon alpha/beta by promoting activation of the JAK/STAT signaling by inhibiting SOCS3 in hepatocellular carcinoma cells
复制标题
6-Hydroxy-3-O-methyl-kaempferol 6-O-glucopyranoside 通过抑制肝细胞癌细胞中的 SOCS3 来促进 JAK/STAT 信号传导的激活，从而增强干扰素 α/β 的抗增殖作用
DOI：
10.1016/j.taap.2017.10.004
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发表时间：
2017
影响因子：
3.8
通讯作者：
Wang Fei
中科院分区：
文献类型：
--
作者：
Wonganan Orawan;He Yu-jiao;Shen Xiao-fei;Wongkrajang Kanjana;Suksamrarn Apichart;Zhang Guo-lin;Wang Fei
细胞因子信号转导抑制因子3（SOCS 3）是I型干扰素（IFN α/β）信号转导的关键负调节因子。小分子抑制SOCS 3可能是增强I型IFN疗效并减少其副作用的新策略。我们建立了一种基于细胞的筛选方法，使用稳定转染有质粒的人肝癌HepG 2细胞，其中荧光素酶报告基因活性由干扰素α刺激的应答元件（ISRE）推动，ISRE是I型IFN诱导的Janus激酶/信号转导和转录激活因子（JAK/STAT）途径活化的特异性识别基序。经筛选，得到6-羟基-3-O-甲基-山奈酚6-O-吡喃葡萄糖苷（6-hydroxy-3-O-methyl-kaempferol 6-O-glucopyranoside，K6 G），其EC_（50）值为3.33 ± 0.04 μM。K6 G可增强JAK 1、Tyk 2和STAT 1/2的磷酸化，但降低STAT 3的磷酸化。K6 G还促进内源性IFN-α调节基因的表达。更有趣的是，K6 G显著降低了SOCS 3的表达，而不影响SOCS 1的表达。K6 G还能增强IFN-α对肝癌细胞的抗增殖作用。这些结果表明，K6 G通过抑制SOCS 3表达激活JAK/STAT信号通路，增强IFN-α对HCC细胞增殖的抑制作用。K6 G值得进一步研究，作为一种新的治疗方法，以提高IFN-α/β的疗效。
Suppressor of cytokine signaling 3 (SOCS3) is a key negative regulator of type I interferon (IFN α/β) signaling. Inhibition of SOCS3 by small molecules may be a new strategy to enhance the efficacy of type I IFN and reduce its side effects. We established a cell-based screening assay using human hepatoma HepG2 cells stably transfected with a plasmid wherein the luciferase reporter activity was propelled by interferon α-stimulated response element (ISRE), which is a motif specifically recognized by type I IFN-induced activation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. After screening our chemical library, 6-hydroxy-3-O-methyl-kaempferol 6-O-glucopyranoside (K6G) was identified to be a potent activator of type I IFN with EC50value of 3.33 ± 0.04 μM. K6G enhanced the phosphorylation of JAK1, Tyk2, and STAT1/2 but decreased the phosphorylation of STAT3. K6G also promoted endogenous IFN-α-regulated genes expression. More interestingly, K6G significantly decreased the expression of SOCS3 without affecting the expression of SOCS1. Furthermore, K6G enhanced the anti-proliferative effect of IFN-α on hepatocellular carcinoma (HCC) cells. These results suggested that K6G potentiated the inhibitory effect of IFN-α on HCC cell proliferation through activation of the JAK/STAT signaling pathway by inhibiting SOCS3 expression. K6G warrants further investigation as a novel therapeutic method to enhance the efficacy of IFN-α/β.