Dietary apigenin potentiates the inhibitory effect of interferon-α on cancer cell viability through inhibition of 26S proteasome-mediated interferon receptor degradation.
Dietary apigenin potentiates the inhibitory effect of interferon-α on cancer cell viability through inhibition of 26S proteasome-mediated interferon receptor degradation.
复制标题
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
DOI：
10.3402/fnr.v60.31288
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发表时间：
2016
影响因子：
3.3
通讯作者：
Wang F
中科院分区：
文献类型：
--
作者：
Li S;Yang LJ;Wang P;He YJ;Huang JM;Liu HW;Shen XF;Wang F
I型干扰素(α/β)具有广泛而有效的免疫调节和抗增殖活性。然而，饮食中的类黄酮类化合物是否通过调节I型干扰素的功能来显示其抗病毒和抗癌特性仍是未知的。这项研究旨在确定芹菜素在I型干扰素介导的抑制癌细胞活性中的作用。芹菜素是一种常见水果和蔬菜中丰富的膳食植物黄酮类化合物。体外研究了芹菜素对已知的I型干扰素信号负调控因子26S蛋白酶体的抑制作用。通过分子对接了解芹菜素与26S蛋白酶体亚基之间的相互作用。研究了芹菜素对JAK/STAT通路、26S蛋白酶体介导的干扰素受体稳定性和癌细胞活力的影响。在基于细胞的实验中，芹菜素被确定为人26S蛋白酶体的有效抑制物。芹菜素抑制人26S蛋白酶体的类糜蛋白酶、半胱氨酸天冬氨酸蛋白酶和类胰蛋白酶的活性，并增加细胞内内源蛋白的泛素化。通过对芹菜素与蛋白酶体的糜蛋白酶(β5亚基)、半胱氨酸天冬氨酸氨基转移酶(β1亚基)和胰蛋白酶(β2亚基)相互作用的计算模拟，结果与观察到的蛋白酶体抑制活性一致。芹菜素增强信号转导和转录激活蛋白(STAT1和STAT2)的磷酸化，促进内源性干扰素-α调节的基因表达。芹菜素抑制干扰素-α刺激的泛素化和I型干扰素受体1的降解。芹菜素还能敏化干扰素-α对宫颈癌HeLa细胞活力的抑制作用。这些结果表明，芹菜素通过抑制26S蛋白酶体介导的α降解而激活JAK/STAT信号通路，从而增强干扰素-JAK对癌细胞活性的抑制作用。这可能为提高干扰素-α/β的疗效提供了一种新的机制。
Type I interferons (IFN-α/β) have broad and potent immunoregulatory and antiproliferative activities. However, it is still known whether the dietary flavonoids exhibit their antiviral and anticancer properties by modulating the function of type I IFNs. This study aimed at determining the role of apigenin, a dietary plant flavonoid abundant in common fruits and vegetables, on the type I IFN-mediated inhibition of cancer cell viability. Inhibitory effect of apigenin on human 26S proteasome, a known negative regulator of type I IFN signaling, was evaluated in vitro. Molecular docking was conducted to know the interaction between apigenin and subunits of 26S proteasome. Effects of apigenin on JAK/STAT pathway, 26S proteasome-mediated interferon receptor stability, and cancer cells viability were also investigated. Apigenin was identified to be a potent inhibitor of human 26S proteasome in a cell-based assay. Apigenin inhibited the chymotrypsin-like, caspase-like, and trypsin-like activities of the human 26S proteasome and increased the ubiquitination of endogenous proteins in cells. Results from computational modeling of the potential interactions of apigenin with the chymotrypsin site (β5 subunit), caspase site (β1 subunit), and trypsin site (β2 subunit) of the proteasome were consistent with the observed proteasome inhibitory activity. Apigenin enhanced the phosphorylation of signal transducer and activator of transcription proteins (STAT1 and STAT2) and promoted the endogenous IFN-α-regulated gene expression. Apigenin inhibited the IFN-α-stimulated ubiquitination and degradation of type I interferon receptor 1 (IFNAR1). Apigenin also sensitized the inhibitory effect of IFN-α on viability of cervical carcinoma HeLa cells. These results suggest that apigenin potentiates the inhibitory effect of IFN-α on cancer cell viability by activating JAK/STAT signaling pathway through inhibition of 26S proteasome-mediated IFNAR1 degradation. This may provide a novel mechanism for increasing the efficacy of IFN-α/β.