孤儿受体 Nur77 的过表达及其受 PCH4 诱导的易位可能抑制恶性神经胶质瘤细胞的生长并诱导细胞凋亡。
Overexpression of the orphan receptor Nur77 and its translocation induced by PCH4 may inhibit malignant glioma cell growth and induce cell apoptosis.
机构信息
Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, ROC.
出版信息
J Surg Oncol. 2011 Apr;103(5):442-50. doi: 10.1002/jso.21809. Epub 2011 Jan 18.
BACKGROUND
In previous study, n-butylidenephthalide (BP), a natural compound from Angelica sinensis, has anti-glioblastoma multiform (GBM) cell effects. In this study, we modified BP structure to increase anti-GBM cell effects. The anti-GBM cell effects of one derivative of BP, (Z)-N-(2-(dimethylamino)ethyl)-2-(3-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)phenoxy)acetamide (PCH4) were tested in vitro and in vivo.
METHODS
MTT assay and PI/Annexin V assay were performed to evaluate the anti-GBM effects of PCH4. The Nur77 expression and translocation were assayed by RT-PCR and Western blot. The Nur77 siRNA was used to downregulate the Nur77 expression. The JNK inhibitor (SP600125) was used to block the JNK pathway.
RESULTS
The anti-GBM effect of PCH4 is four times more than BP. The IC(50) of PCH4 on DBTRG-05MG cells was 50 µg/ml. Nur77 expression and translocation from the nucleus to the cytoplasm were important in PCH4-induced apoptosis. Furthermore, the downregulation of PCH4-induced Nur77 expression by Nur77 siRNA reduced PCH4-induced apoptosis. In addition, PCH4-induced apoptosis was associated with the JNK pathway. The JNK inhibitor, SP600125, inhibited Nur77 mRNA expression and reduced PCH4-induced apoptosis.
CONCLUSIONS
In conclusion, PCH4, a derivative of BP, induced Nur77-mediated apoptosis via the JNK pathway and this mechanism, which is different from that of BP, may explain the increase in the anti-tumor effects on GBM.
背景
在之前的研究中，藁本内酯（BP），一种来自当归的天然化合物，具有抗胶质母细胞瘤（GBM）细胞的作用。在这项研究中，我们修改了 BP 的结构以提高其抗 GBM 细胞的效果。BP 的一种衍生物（Z）-N-（2-（二甲氨基）乙基）-2-（3-（（3-氧代异苯并呋喃-1（3H）-亚基）甲基）苯氧基）乙酰胺（PCH4）的抗 GBM 细胞作用在体外和体内进行了测试。
方法
MTT 法和 PI/Annexin V 法检测 PCH4 的抗 GBM 作用。通过 RT-PCR 和 Western blot 检测 Nur77 的表达和易位。用 Nur77 siRNA 下调 Nur77 表达。用 JNK 抑制剂（SP600125）阻断 JNK 通路。
结果
PCH4 的抗 GBM 作用是 BP 的四倍。PCH4 对 DBTRG-05MG 细胞的 IC50 为 50μg/ml。PCH4 诱导的细胞凋亡过程中 Nur77 的表达和从细胞核向细胞质的易位是重要的。此外，Nur77 siRNA 下调 PCH4 诱导的 Nur77 表达减少了 PCH4 诱导的细胞凋亡。此外，PCH4 诱导的细胞凋亡与 JNK 通路有关。JNK 抑制剂 SP600125 抑制 Nur77 mRNA 表达并减少 PCH4 诱导的细胞凋亡。
结论
总之，BP 的衍生物 PCH4 通过 JNK 通路诱导 Nur77 介导的细胞凋亡，这种机制与 BP 不同，可能解释了其对 GBM 肿瘤的抗肿瘤作用增强的原因。
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