Orphan nuclear receptor, Nurr-77 was a possible target gene of butylidenephthalide chemotherapy on glioblastoma multiform brain tumor

Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan.
Journal of Neurochemistry (Impact Factor: 4.28). 06/2008; 106(3):1017-26. DOI: 10.1111/j.1471-4159.2008.05432.x
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ABSTRACT 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.

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Available from: Shinn-Zong Lin, Sep 05, 2014
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    • "However, it was reported that K-Ras (phosphorylated on Ser181 by protein kinase C) promotes cell death by interaction with inositol triphosphate receptors (IP3Rs) on the endoplasmic reticulum (ER) membrane, which in turn impairs the pro-survival effect of Bcl-X L to stimulate the IP3R-mediated transfer of Ca 2+ from the ER to mitochondria [19] [20]. At the same time, mitochondrial targeting of NR4A1 and induction of apoptotic cell death has been observed in immature thymocytes and T cell hybridomas [21] [22] as well as in various cancer cell types, e.g. from the prostate [14], lung [23], stomach [24] [25], brain [26] [27] and ovary [28] [29]. Fig. 4 depicts agents that induce translocation of NR4A1 to different cellular compartments. "
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    ABSTRACT: The orphan nuclear receptor NR4A1/Nur77/TR3/NGFIB acts primarily as a transcription factor to regulate the expression of multiple genes. However, increasing research attention has recently been given to non-genomic activities of NR4A1. The first description of a non-genomic action of NR4A1 referred to the conversion of anti-apoptotic Bcl-2 into a pro-apoptotic protein by direct interaction with NR4A1. In response to certain apoptotic stimuli, NR4A1 translocates from the nucleus to the mitochondrial outer membrane (MOM) where it associates with Bcl-2 and thereby causes apoptosis. Afterwards, it appeared that NR4A1 could also bind and convert other anti-apoptotic Bcl-2 family members. The latest studies indicate a significant role of NR4A1 in the process of autophagy. For example, a new NR4A1-mediated pathway specific for melanoma cells has been described where NR4A1 interacts with the adenine nucleotide translocase 1 (ANT1) on the mitochondrial inner membrane (MIM) leading to induction of the autophagy pathway. Moreover, NR4A1 interaction with cytoplasmic p53 may also contribute to the induction of autophagy. In addition to mitochondria, NR4A1 could be translocated to the outer membrane of the endoplasmic reticulum (ER) and associate with Bcl-2 or translocon-associated protein subunit γ (TRAPγ) causing ER stress-induced apoptosis. NR4A1 also contributes to the proteasomal degradation of β-catenin in colon cancer cells in vitro and in vivo, as well as to the stabilization of hypoxia-inducible factor-1α (HIF-1α) under non-hypoxic conditions. This review summarizes research findings on non-genomic effects of NR4A1 in normal and cancer cells.
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    • "Isolation of total RNA, cDNA synthesis, and amplification reactions were carried out as described [28]. Total RNA was isolated from cells using the RNeasy kit (Qiagen), and cDNA was synthesized from 10 μg of total RNA using the Advantage RT-for-PCR kit (Clontech). "
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    • "Previously oligodeoxynucleotide-based microarray was used to screen the anti-tumor mechanism of BP in glioblastoma multiforme brain tumor cells. It was found that the induction of Nur77 gene expression using BP induced the cancer cell death (Lin et al., 2008). A later report assessed the possible role of Nur77-in- duced apoptosis in hepatocellular carcinoma cells and the result implicated the PI3K/AKT/GSK3b signaling pathways may be involved in the regulation of BP-induced apoptosis in hepatocellular carcinoma (Chen et al., 2008). "
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    ABSTRACT: Although numerous studies have shown the cancer-preventive properties of butylidenephthalide (BP), there is little report of BP affecting human prostate cancer cells. In the present study, proteomic-based approaches were used to elucidate the anticancer mechanism of BP in LNCaP human prostate cancer cells. BP treatment decreased the viability of LNCaP human prostate cancer cells in a concentration- and time-dependent manner, which was correlated with G0/G1 phase cell cycle arrest. Increased cell cycle arrest was associated with a decrease in the level of CCND1, CDK2, and PCNA proteins and an increase in the level of CDKN2A, CDKN1A, and SFN proteins. Proteomic studies revealed that among forty eight differentially expressed proteins, twenty five proteins were down-regulated and twenty three proteins were up-regulated and these proteins fall into one large protein protein interaction network. Among these proteins, FAS, AIFM1, BIK, CYCS, SFN, PPP2R1A, CALR, HSPA5, DDIT3, and ERN1 are apoptosis and endoplasmic reticulum (ER) stress associated proteins. Proteomic data suggested that multiple signaling pathways including FAS-dependent pathway, mitochondrial pathway, and ER stress pathway are involved in the apoptosis induced by BP.
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