Natural product-derived icaritin exerts anti-glioblastoma effects by positively modulating estrogen receptor β
Natural product-derived icaritin exerts anti-glioblastoma effects by positively modulating estrogen receptor β
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天然产物淫羊藿素通过正向调节雌激素受体β发挥抗胶质母细胞瘤作用
DOI：
10.3892/etm.2020.8571
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发表时间：
2020-04-01
影响因子：
2.7
通讯作者：
Zhou, Yuehan
中科院分区：
文献类型：
--
作者：
Li, Xiaowen;Zhang, Weiwei;Zhou, Yuehan
胶质母细胞瘤是中枢神经系统最常见的恶性肿瘤，患者通常预后不良。先前的研究表明胶质母细胞瘤的发生存在性别差异；与男性相比，女性的患病风险较低，这表明雌激素可能具有保护作用。淫羊藿苷是一种从淫羊藿属中药中提取的异戊烯基黄酮衍生物，它能选择性地调节雌激素受体（ER）并具有抗癌特性。本研究的目的是探讨淫羊藿苷对胶质母细胞瘤的保护作用及其潜在机制，尤其关注其与雌激素受体的关联。结果表明，淫羊藿苷以剂量和时间依赖的方式抑制C6和U87 - MG胶质母细胞瘤细胞的生长。在浓度为12.5μM时，淫羊藿苷诱导细胞凋亡，其特征是半胱天冬酶3、7、8和9以及聚（ADP - 核糖）聚合酶的裂解形式表达增加，BCL2凋亡调节因子下调以及BCL2相关X凋亡调节因子表达上调。此外，淫羊藿苷抑制C6和U87 - MG细胞的迁移。基质金属蛋白酶（MMP）-2和MMP - 9的蛋白表达水平在淫羊藿苷处理后也下调。此外，淫羊藿苷处理增加了雌激素受体（ER）β以及磷酸酶和张力蛋白（PTEN）同源肿瘤抑制蛋白的表达，从而降低了PTEN下游靶点；蛋白激酶B（Akt）和磷酸化Akt的表达。后续实验表明，淫羊藿苷与17β - 雌二醇协同抑制胶质母细胞瘤细胞的生长，并且用ERβ特异性拮抗剂ICI 182,780抑制ERβ会减弱淫羊藿苷的抗胶质母细胞瘤作用。总之，本研究结果表明，淫羊藿苷的抗胶质母细胞瘤作用可能是通过其对ERβ的调节介导的。
Glioblastoma is the most common malignancy of the central nervous system, and patients typically have a poor prognosis. Previous studies indicate a gender bias in the development of glioblastoma; women are at a lower risk compared with men, suggesting that estrogen may confer protective effects. Icaritin, a prenylflavonoid derivative from a Chinese herb of the Epimedium genus, selectively regulates the estrogen receptor (ER) and possesses anti-cancer properties. The aim of the present study was to investigate the protective effects of icaritin on glioblastoma and its underlying mechanisms, with a particular focus on its association with the ER. The results demonstrated that icaritin inhibited the growth of C6 and U87-MG glioblastoma cells in a dose- and time-dependent manner. At a concentration of 12.5 mu M, icaritin induced apoptosis, which was characterized by the increased expression of the cleaved forms of caspases 3, 7, 8 and 9 and poly (ADP-ribose) polymerase, downregulation of BCL2 apoptosis regulator and upregulation of BCL2-associated X, apoptosis regulator expression. Additionally, icaritin inhibited the migration of C6 and U87-MG cells. The protein expression levels of matrix metalloproteinase (MMP)-2 and MMP-9 were also downregulated following icaritin treatment. Furthermore, icaritin treatment increased the expression of estrogen receptor (ER)beta and the phosphatase and tensin (PTEN) homolog oncoprotein, thus reducing the expression of downstream targets of PTEN; protein kinase B (Akt) and phosphorylated Akt. Subsequent experiments demonstrated that icaritin cooperates with 17 beta-estradiol to inhibit the growth of glioblastoma cells, and the inhibition of ER beta with the ER beta-specific antagonist ICI 182,780, attenuated the anti-glioblastoma effects of icaritin. In conclusion, the results of the present study demonstrate that the anti-glioblastoma effects of icaritin may be mediated by its modulation of ER beta.