Overexpression of the orphan receptor Nur77 and its translocation induced by PCH4 may inhibit malignant glioma cell growth and induce cell apoptosis.
Abstract | 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.
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Authors | Li-Fu Chang, Po-Cheng Lin, Li-Ing Ho, Po-Yen Liu, Wan-Chen Wu, I-Ping Chiang, Hui-Wen Chang, Shinn-Zong Lin, Yeu-Chern Harn, Horng-Jyh Harn, Tzyy-Wen Chiou |
Journal | Journal of surgical oncology
(J Surg Oncol)
Vol. 103
Issue 5
Pg. 442-50
(Apr 2011)
ISSN: 1096-9098 [Electronic] United States |
PMID | 21246566
(Publication Type: Journal Article)
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Copyright | Copyright © 2011 Wiley-Liss, Inc. |
Chemical References |
- Benzofurans
- DNA-Binding Proteins
- Ethylamines
- N-(2-(dimethylamino)ethyl)-2-(3-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)phenoxy)acetamide
- NR4A2 protein, human
- NR4A3 protein, human
- Nuclear Receptor Subfamily 4, Group A, Member 1
- Nuclear Receptor Subfamily 4, Group A, Member 2
- Phthalic Anhydrides
- RNA, Messenger
- RNA, Small Interfering
- Receptors, Steroid
- Receptors, Thyroid Hormone
- Luciferases
- MAP Kinase Kinase 4
- butylidenephthalide
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Topics |
- Angelica sinensis
(chemistry)
- Animals
- Apoptosis
(drug effects)
- Benzofurans
(pharmacology)
- Blotting, Western
- Brain Neoplasms
(drug therapy, metabolism, pathology)
- Cell Proliferation
(drug effects)
- DNA-Binding Proteins
(antagonists & inhibitors, genetics, metabolism)
- Ethylamines
(pharmacology)
- Flow Cytometry
- Glioblastoma
(drug therapy, metabolism, pathology)
- Humans
- Luciferases
(metabolism)
- MAP Kinase Kinase 4
(antagonists & inhibitors, metabolism)
- Mice
- Mice, Nude
- Nuclear Receptor Subfamily 4, Group A, Member 1
(antagonists & inhibitors, genetics, metabolism)
- Nuclear Receptor Subfamily 4, Group A, Member 2
(antagonists & inhibitors, genetics, metabolism)
- Phthalic Anhydrides
(chemistry, pharmacology)
- Protein Transport
(drug effects)
- RNA, Messenger
(genetics)
- RNA, Small Interfering
(genetics)
- Receptors, Steroid
(antagonists & inhibitors, genetics, metabolism)
- Receptors, Thyroid Hormone
(antagonists & inhibitors, genetics, metabolism)
- Reverse Transcriptase Polymerase Chain Reaction
- Signal Transduction
- Tumor Cells, Cultured
- Xenograft Model Antitumor Assays
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