Overexpression of the orphan receptor Nur77 and its translocation induced by PCH4 may inhibit malignant glioma cell growth and induce cell apoptosis

Chang, Li-Fu; Lin, Po Ting; Ho, Li‐Ing; Liu, Po-Yen; Wu, Wan-Chen; Chiang, I-Ping; Chang, Hui‐Wen; Lin, Shinn‐Zong; Harn, Yeu-Chern; Harn, Horng‐Jyh; Chiou, Tzyy‐Wen

doi:10.1002/jso.21809

Cited by 39 publications

(31 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since it is well established that certain genes/proteins listed in Table 2 can exert different roles according to the cellular context [1] [110] [162] (see file S2 for more details), we also tried to avoid considering functional results obtained from excessive pathological stimuli, which could alter the physiological native role of a gene/protein. For instance in [60] the neurons were treated with Camptothecin to cause DNA damage and the Cbp/p300-interacting transactivator 2 , also known as Cited2 , was related to the activation of apoptosis: we found these circumstances too dissimilar from the gabazine-treatment of the present work and therefore we decided not to consider this as a functional evidence.…”

Section: Resultsmentioning

confidence: 99%

Early Phase of Plasticity-Related Gene Regulation and SRF Dependent Transcription in the Hippocampus

2013

View full text Add to dashboard Cite

Hippocampal organotypic cultures are a highly reliable in vitro model for studying neuroplasticity: in this paper, we analyze the early phase of the transcriptional response induced by a 20 µM gabazine treatment (GabT), a GABA-Ar antagonist, by using Affymetrix oligonucleotide microarray, RT-PCR based time-course and chromatin-immuno-precipitation. The transcriptome profiling revealed that the pool of genes up-regulated by GabT, besides being strongly related to the regulation of growth and synaptic transmission, is also endowed with neuro-protective and pro-survival properties. By using RT-PCR, we quantified a time-course of the transient expression for 33 of the highest up-regulated genes, with an average sampling rate of 10 minutes and covering the time interval [10∶90] minutes. The cluster analysis of the time-course disclosed the existence of three different dynamical patterns, one of which proved, in a statistical analysis based on results from previous works, to be significantly related with SRF-dependent regulation (p-value<0.05). The chromatin immunoprecipitation (chip) assay confirmed the rich presence of working CArG boxes in the genes belonging to the latter dynamical pattern and therefore validated the statistical analysis. Furthermore, an in silico analysis of the promoters revealed the presence of additional conserved CArG boxes upstream of the genes Nr4a1 and Rgs2. The chip assay confirmed a significant SRF signal in the Nr4a1 CArG box but not in the Rgs2 CArG box.

show abstract

Section: Resultsmentioning

confidence: 99%

Early Phase of Plasticity-Related Gene Regulation and SRF Dependent Transcription in the Hippocampus

2013

View full text Add to dashboard Cite

show abstract

“…Several drugs already in clinical use are now recognized to induce nuclear export of NR4A1, including 5-fluorouracil (5-FU) and certain NSAIDs (15). Novel drugs targeting nuclear export of NR4A1 include n-butylenephthalide (BP) and cytosporone B. BP and its derivatives (PCH4) have shown therapeutic potential in glioblastoma multiforme, in vitro and in vivo, and in oral squamous cell carcinoma in vitro (32). PCH4 induces apoptosis in oral squamous cell carcinoma and glioblastoma multiforme cell lines in a mechanism dependent on PCH4-mediated increased NR4A1 expression and cytoplasmic translocation (32,33).…”

Section: Nr4a Receptors: Identified Roles In Human Cancermentioning

confidence: 99%

“…Novel drugs targeting nuclear export of NR4A1 include n-butylenephthalide (BP) and cytosporone B. BP and its derivatives (PCH4) have shown therapeutic potential in glioblastoma multiforme, in vitro and in vivo, and in oral squamous cell carcinoma in vitro (32). PCH4 induces apoptosis in oral squamous cell carcinoma and glioblastoma multiforme cell lines in a mechanism dependent on PCH4-mediated increased NR4A1 expression and cytoplasmic translocation (32,33). Cytosporone B, a compound isolated from fungi, is a ligand for NR4A1 and induces apoptosis by transactivation of NR4A1 target genes and by inducing expression and mitochondrial localization of NR4A1 in vivo and in vitro (34).…”

Section: Nr4a Receptors: Identified Roles In Human Cancermentioning

confidence: 99%

Molecular Pathways: The Role of NR4A Orphan Nuclear Receptors in Cancer

Mohan

Aherne

Rogers

et al. 2012

Clinical Cancer Research

155

142

View full text Add to dashboard Cite

Nuclear receptors are of integral importance in carcinogenesis. Manipulation of classic ligand-activated nuclear receptors, such as estrogen receptor blockade in breast cancer, is an important established cancer therapy. Orphan nuclear receptors, such as nuclear family 4 subgroup A (NR4A) receptors, have no known natural ligand(s). These elusive receptors are increasingly recognized as molecular switches in cell survival and a molecular link between inflammation and cancer. NR4A receptors act as transcription factors, altering expression of downstream genes in apoptosis (Fas-ligand, TRAIL), proliferation, DNA repair, metabolism, cell migration, inflammation (interleukin-8), and angiogenesis (VEGF). NR4A receptors are modulated by multiple cell-signaling pathways, including protein kinase A/CREB, NF-kB, phosphoinositide 3-kinase/AKT, c-jun-NH 2 -kinase, Wnt, and mitogen-activated protein kinase pathways. NR4A receptor effects are context and tissue specific, influenced by their levels of expression, posttranslational modification, and interaction with other transcription factors (RXR, PPAR-¡). The subcellular location of NR4A "nuclear receptors" is also important functionally; novel roles have been described in the cytoplasm where NR4A proteins act both indirectly and directly on the mitochondria to promote apoptosis via Bcl-2. NR4A receptors are implicated in a wide variety of malignancies, including breast, lung, colon, bladder, and prostate cancer; glioblastoma multiforme; sarcoma; and acute and/or chronic myeloid leukemia. NR4A receptors modulate response to conventional chemotherapy and represent an exciting frontier for chemotherapeutic intervention, as novel agents targeting NR4A receptors have now been developed. This review provides a concise clinical overview of current knowledge of NR4A signaling in cancer and the potential for therapeutic manipulation.

show abstract

“…The natural compound n-butylidenephthalide (BP), isolated from the chloroform extract of Angelica sinensis, has been reported to have antitumor activity in glioblastoma multiforme (GBM), [1][2][3][4] prostate cancer, 5,6 oral squamous cell carcinoma, 7 lung cancer, 8 and hepatoma. 9 In particular, BP has been developed to treat brain tumors due to its ability to permeate through the blood-brain barrier and enter into the brain.…”

Section: Introductionmentioning

confidence: 99%

“…1 BP induces Nur77-mediated apoptosis via the protein kinase C/JNK pathway. 4,7,9,10 BP downregulates the expression of S-phase kinase-associated protein (Skp2), which leads to an increase in p16 and p21 expression, causing G 0 /G 1 arrest. 2 BP inhibits telomerase activity by repressing hTERT transcriptional activity via the downregulation of Sp1 or AP-2 expression.…”

Section: Introductionmentioning

confidence: 99%

Liposomal n-butylidenephthalide protects the drug from oxidation and enhances its antitumor effects in glioblastoma multiforme

Lin¹,

Chang²,

Huang³

et al. 2015

IJN

View full text Add to dashboard Cite

Background The natural compound n -butylidenephthalide (BP) can pass through the blood–brain barrier to inhibit the growth of glioblastoma multiforme tumors. However, BP has an unstable structure that reduces its antitumor activity and half-life in vivo. Objective The aim of this study is to design a drug delivery system to encapsulate BP to enhance its efficacy by improving its protection and delivery. Methods To protect its structural stability against protein-rich and peroxide solutions, BP was encapsulated into a lipo-PEG-PEI complex (LPPC). Then, the cytotoxicity of BP/LPPC following preincubation in protein-rich, acid/alkaline, and peroxide solutions was analyzed by MTT. Cell uptake of BP/LPPC was also measured by confocal microscopy. The therapeutic effects of BP/LPPC were analyzed in xenograft mice following intratumoral and intravenous injections. Results When BP was encapsulated in LPPC, its cytotoxicity was maintained following preincubation in protein-rich, acid/alkaline, and peroxide solutions. The cytotoxic activity of encapsulated BP was higher than that of free BP (~4.5- to 8.5-fold). This increased cytotoxic activity of BP/LPPC is attributable to its rapid transport across the cell membrane. In an animal study, a subcutaneously xenografted glioblastoma multiforme mouse that was treated with BP by intratumoral and intravenous administration showed inhibited tumor growth. The same dose of BP/LPPC was significantly more effective in terms of tumor inhibition. Conclusion LPPC encapsulation technology is able to protect BP’s structural stability and enhance its antitumor effects, thus providing a better tool for use in cancer therapy.

show abstract

Overexpression of the orphan receptor Nur77 and its translocation induced by PCH4 may inhibit malignant glioma cell growth and induce cell apoptosis

Abstract: 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.

Cited by 39 publications

References 21 publications

Early Phase of Plasticity-Related Gene Regulation and SRF Dependent Transcription in the Hippocampus

Early Phase of Plasticity-Related Gene Regulation and SRF Dependent Transcription in the Hippocampus

Molecular Pathways: The Role of NR4A Orphan Nuclear Receptors in Cancer

Liposomal n-butylidenephthalide protects the drug from oxidation and enhances its antitumor effects in glioblastoma multiforme

Contact Info

Product

Resources

About