Orphan nuclear receptor, Nurr-77 was a possible target gene of butylidenephthalide chemotherapy on glioblastoma multiform brain tumor.
The natural compound n-butylidenephthalide (BP), which is isolated from the chloroform extract of Angelica sinensis, has been investigated for its antitumoral effects on glioblastoma multiform (GBM) brain tumors both in vitro and in vivo. To determine the mechanism of BP-induced growth arrest and apoptosis, we examined BP-induced changes in gene expression by microarray screening using human GBM brain tumor cells. This analysis identified several BP-inducible genes, including the nuclear receptors NOR-1, Nurr1, and Nur77. Among these genes, Nur77 is particularly interesting because it plays an important role in the apoptotic processes in various tumor cell lines. BP was able to increase Nur77 mRNA and protein expression in a time-dependent manner. After BP treatment in GBM 8401 cells, Nur77 translocated from the nucleus to the cytoplasm, the cytochrome c was released from the mitochondria, and caspase 3 became activated. Furthermore, using Nur77 promoter-luciferase assay, BP increased Nur77 was AP1 related. Inhibition of BP-induced Nur77 expression by Nur77 short interfering RNA blocked BP-induced apoptosis in GBM 8401 cells, suggesting that the induction of Nur77 negatively affected GBM 8401 cell survival. In summary, our results suggest that up-regulation of Nur77 may explain the antitumoral activity of BP in brain tumor cells.
Lin
Po-Cheng
PC
Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan.
Chen
Yi-Lin
YL
Chiu
Shao-Chih
SC
Yu
Yung-Luen
YL
Chen
Shee-Ping
SP
Chien
Min-Hui
MH
Chen
Kuan-Yen
KY
Chang
Wen-Liang
WL
Lin
Shinn-Zong
SZ
Chiou
Tzyy-Wen
TW
Harn
Horng-Jyh
HJ
D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D018390:Gene Targeting / Q000379:methods*; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D051379:Mice; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010796:Phthalic Anhydrides / Q000008:administration & dosage*; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000235:genetics; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D004268:DNA-Binding Proteins; C539821:NR4A1 protein, human; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010796:Phthalic Anhydrides; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; C026105:butylidenephthalide