Xanthatin induces glioma cell apoptosis and inhibits tumor growth via activating endoplasmic reticulum stress-dependent CHOP pathway
Xanthatin induces glioma cell apoptosis and inhibits tumor growth via activating endoplasmic reticulum stress-dependent CHOP pathway
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DOI：
10.1038/s41401-019-0318-5
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发表时间：
2020-03-01
影响因子：
8.2
通讯作者：
Feng, Li-jie
中科院分区：
文献类型：
--
作者：
Ma, Yu-yang;Di, Ze-min;Feng, Li-jie
黄苷是从苍耳中提取的一种天然倍半萜内酯，其对多种癌细胞显示出显著的抗肿瘤活性。本研究通过体外和体内实验观察黄嘌呤对胶质瘤细胞生长的影响，并探讨其作用机制。在大鼠胶质瘤C6和人胶质瘤U251细胞系中，黄嘌呤（1-15 μ M）剂量依赖性地抑制细胞活力，对细胞周期没有明显影响。此外，黄嘌呤处理剂量依赖性地诱导胶质瘤细胞凋亡。在荷C6胶质瘤异种移植瘤的裸鼠中，给予黄嘌呤（10、20、40 mg中心点kg（-1）中心点d（-1），ip，持续2周）剂量依赖性地抑制肿瘤生长，但不影响体重。更重要的是，黄嘌呤处理显著增加了胶质瘤细胞系以及C6异种移植物中内质网（ER）应激相关标志物的表达水平，包括葡萄糖调节蛋白78、C/EBP同源蛋白（CHOP）、激活因子4、激活转录因子6、剪接的X-box结合蛋白-1、磷酸化蛋白激酶R样内质网激酶、和磷酸化真核起始因子2a。预处理C6胶质瘤细胞与ER应激抑制剂4-苯基丁酸（4-PBA，7毫米）或敲低CHOP使用小干扰RNA显着衰减黄嘌呤诱导的细胞凋亡和增加促凋亡caspase-3。这些结果表明，黄嘌呤诱导胶质瘤细胞凋亡，抑制肿瘤生长，通过激活ER应激相关的未折叠蛋白反应途径，涉及CHOP诱导。黄嘌呤在脑胶质瘤的治疗中具有广阔的应用前景。
Xanthatin is a natural sesquiterpene lactone purified from Xanthium strumarium L., which has shown prominent antitumor activity against a variety of cancer cells. In the current study, we investigated the effect of xanthatin on the growth of glioma cells in vitro and in vivo, and elucidated the underlying mechanisms. In both rat glioma C6 and human glioma U251 cell lines, xanthatin (1-15 mu M) dose-dependently inhibited cell viability without apparent effect on the cell cycle. Furthermore, xanthatin treatment dose-dependently induced glioma cell apoptosis. In nude mice bearing C6 glioma tumor xenografts, administration of xanthatin (10, 20, 40 mg center dot kg(-1)center dot d(-1), ip, for 2 weeks) dose-dependently inhibited the tumor growth, but did not affect the body weight. More importantly, xanthatin treatment markedly increased the expression levels of the endoplasmic reticulum (ER) stress-related markers in both the glioma cell lines as well as in C6 xenografts, including glucose-regulated protein 78, C/EBP-homologous protein (CHOP), activating factor 4, activating transcription factor 6, spliced X-box binding protein-1, phosphorylated protein kinase R-like endoplasmic reticulum kinase, and phosphorylated eukaryotic initiation factor 2a. Pretreatment of C6 glioma cells with the ER stress inhibitor 4-phenylbutyric acid (4-PBA, 7 mM) or knockdown of CHOP using small interfering RNA significantly attenuated xanthatin-induced cell apoptosis and increase of proapoptotic caspase-3. These results demonstrate that xanthatin induces glioma cell apoptosis and inhibits tumor growth via activating the ER stress-related unfolded protein response pathway involving CHOP induction. Xanthatin may serve as a promising agent in the treatment of human glioma.