Orphan nuclear receptor, Nurr-77 was a possible target gene of butylidenephthalide chemotherapy on glioblastoma multiform brain tumor.
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.
SourceAvailable from: Alicja Pawlak[Show abstract] [Hide abstract]
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.Steroids 12/2014; 95. DOI:10.1016/j.steroids.2014.12.020 · 2.72 Impact Factor
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ABSTRACT: As a transcriptional factor, Nur77 has sparked interests across different research fields in recent years. A number of studies have demonstrated the functional complexity of Nur77 in mediating survival/apoptosis in a variety of cells, including tumor cells. Conflicting observations also exist in clinical reports, in that TR3 behaves like an oncogene in tumors of the GI tract, lung, and breast, that is negatively associated with tumor stage and patient prognosis; while functions as a tumor suppressor gene in malignancies of the hematological and lymphatic system, skin, and ovary whose malfunction results in carcinogenesis. This chapter summarizes the apparent opposing effects of Nur77 on cells and explicates the mechanisms that determine the functional preference of Nur77. We conclude that in addition to cell type and agent context, other factors such as cellular localization, signaling pathway, and posttranslational modification also determine the final effects of Nur77 on cells.International review of cell and molecular biology 01/2014; 313:219-58. DOI:10.1016/B978-0-12-800177-6.00007-4 · 4.52 Impact Factor
JAIDS Journal of Acquired Immune Deficiency Syndromes 01/2011; 56:97. DOI:10.1097/01.qai.0000397407.14534.2e · 4.39 Impact Factor