Broussochalcone A Is a Novel Inhibitor of the Orphan Nuclear Receptor NR4A1 and Induces Apoptosis in Pancreatic Cancer Cells.
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ABSTRACT:
SUBMITTER: Lee HS
PROVIDER: S-EPMC8073833 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:UnlabelledNR4A1 (Nur77, TR3) is an orphan nuclear receptor that is overexpressed in pancreatic cancer and exhibits pro-oncogenic activity. RNA interference of NR4A1 expression in Panc-1 cells induced apoptosis and subsequent proteomic analysis revealed the induction of several markers of endoplasmic reticulum stress, including glucose-related protein 78 (GRP78), CCAAT/enhancer-binding protein-homologous protein (CHOP), and activating transcription factor-4 (ATF-4). Treatment of pancreatic cancer cells with the NR4A1 antagonist 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) gave similar results. Moreover, both NR4A1 knockdown and DIM-C-pPhOH induced reactive oxygen species (ROS), and induction of ROS and endoplasmic reticulum stress by these agents was attenuated after cotreatment with antioxidants. Manipulation of NR4A1 expression coupled with gene expression profiling identified a number of ROS metabolism transcripts regulated by NR4A1. Knockdown of one of these transcripts, thioredoxin domain containing 5 (TXNDC5), recapitulated the elevated ROS and endoplasmic reticulum stress; thus, demonstrating that NR4A1 regulates levels of endoplasmic reticulum stress and ROS in pancreatic cancer cells to facilitate cell proliferation and survival. Finally, inactivation of NR4A1 by knockdown or DIM-C-pPhOH decreased TXNDC5, resulting in activation of the ROS/endoplasmic reticulum stress and proapoptotic pathways.ImplicationsThe NR4A1 receptor is pro-oncogenic, regulates the ROS/endoplasmic reticulum stress pathways, and inactivation of the receptor represents a novel pathway for inducing cell death in pancreatic cancer.
| S-EPMC4407472 | biostudies-literature
Project description:β1-Integrin is highly expressed and is a negative prognostic factor for colon and pancreatic cancer patients and the gene plays a functional role in cell migration and invasion. In this study, we demonstrate that β1-integrin expression is regulated in pancreatic and colon cancer cells by the pro-oncogenic orphan nuclear receptor 4A1 (NR4A1, Nur77, TR3) and knockdown of this receptor by RNA interference decreases β1-integrin protein and mRNA expression, α5-integrin, and also expression of β1-integrin-dependent phosphorylation of FAK (pFak). Knockdown of NR4A1 also decreased migration and fibronectin-induced adhesion in pancreatic (Panc1, L3.6 pL, and MiaPaCa2) and colon (RKO and SW480) cancer cells. 1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methane (C-DIM) compounds containing p-hydroxy (DIM-C-pPhOH) and p-carbomethoxy (DIM-C-pPhCO2 Me) groups are NR4A1 ligands that act as antagonists for this receptor. Treatment of pancreatic and colon cancer cells with DIM-C-pPhOH or DIM-C-pPhCO2 Me mimics the effects of NR4A1 knockdown and decreases β1-integrin expression, β1-integrin regulated genes and responses including migration and adhesion. The results demonstrate a novel method for targeting β1-integrin in colon and pancreatic cancer cells and indicate possible clinical applications for C-DIM/NR4A1 antagonists for pancreatic and colon cancer therapy.
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Project description:A 4.1 μs molecular dynamics simulation of the NR4A1 (hNur77) apo-protein has been undertaken and a previously undetected druggable pocket has become apparent that is located remotely from the 'traditional' nuclear receptor ligand-binding site. A NR4A1/bis-indole ligand complex at this novel site has been found to be stable over 1 μs of simulation and to result in an interesting conformational transmission to a remote loop that has the capacity to communicate with a NBRE within a RXR-α/NR4A1 heterodimer. Several features of the simulations undertaken indicate how NR4A1 can be affected by alternate-site modulators.
| S-EPMC4535767 | biostudies-literature
Project description:NR4A1 (Nur77, TR3) is an orphan nuclear receptor that is overexpressed in pancreatic cancer cells and tumors and exhibits pro-oncogenic activity. Knockdown of NR4A1 by RNA interference (siNR4A1) in Panc1 cells and analysis of the proteome resulted in induction of several markers of endoplasmic reticulum (ER) stress including glucose-related protein 78 (GRP78), CCAAT/enhancer-binding protein-homologous protein (CHOP), activating transcription factor-3 (ATF-3) and AFT-6. These effects were accompanied by induction of apoptosis and similar results were observed after treatment of pancreatic cancer cells with the known inactivator of NR4A1, 1,1-bis(3’-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH). Both siNR4A1 (transfected) and DIM-C-pPhOH also induced reactive oxygen species (ROS) and induction of ROS and ER stress by these agents was attenuated after cotreatment with antioxidants. Transfection of Panc1 cells with siNR4A1 follow by analysis of gene expression by arrays identified ROS metabolism genes regulated by NR4A1. Knockdown of one of these genes, thioredoxin domain containing 5 (TXNDC5) also resulted in induction of ROS and ER stress demonstrating that NR4A1 regulates levels of ER stress and ROS in pancreatic cancer cells to facilitate cell proliferation and survival. Inactivation of this receptor by siNR4A1 or DIM-C-pPhOH decreases TXNDC5 resulting in activation of ROS/ER stress and pro-apoptotic pathways and represents a novel pathway for inducing cell death in pancreatic cancer cells. Two groups of samples are included: 1. siControl; 2. siNR4A1 treatment in PAC1 cell. Transfection of Panc1 cells with siNR4A1 follow by analysis of gene expression by arrays identified ROS metabolism genes regulated by NR4A1.
| S-ECPF-GEOD-46994 | biostudies-other
Project description:Piperlongumine and derivatives are being developed as anticancer agents which act primarily as inducers of reactive oxygen species (ROS) in cancer cell lines. Many of the anticancer activities of piperlongumine resemble those observed for bis-indole derived compounds that bind the orphan nuclear receptor 4A1 (NR4A1) and act as inverse receptor agonists to inhibit NR4A1-regulated pro-oncogenic pathways and genes. In this study we show that like other NR4A1 inverse agonists piperlongumine inhibited RKO, SW480 and HCT116 colon cancer cell growth migration and invasion and induced apoptosis. Piperlongumine also downregulated the pro-reductant isocitrate dehydrogenase 1 (IDH1) and thioredoxin domain-containing 5 (TXNDC5) gene products resulting in the induction of ROS as previously observed for other inverse NR4A1 agonists. ROS also induced sestrin2 and this resulted in activation of AMPK phosphorylation and inhibition of mTOR pathway signaling. It has previously been reported that these pathways/genes are also regulated by inverse NR4A1 agonists or by knockdown of NR4A1. We also observed that piperlongumine directly bound NR4A1, inhibited NR4A1-dependent transactivation and interactions of the NR4A1/Sp1 complex bound to the GC-rich promoter of the NR4A1-regulated G9a gene.
| S-EPMC10551445 | biostudies-literature
Project description:NR4A1 (Nur77, TR3) is overexpressed in pancreatic tumors and activation of TR3 by 1,1-bis(3'-indolyl)-1-(p-methoxyphenyl)methane (DIM-C-pPhOCH(3)) inhibits cell and tumor growth and induces apoptosis. Microarray analysis demonstrates that in L3.6pL pancreatic cancer cells DIM-C-pPhOCH(3) induces genes associated with metabolism, homeostasis, signal transduction, transcription, stress, transport, immune responses, growth inhibition and apoptosis. Among the most highly induced growth inhibitory and proapoptotic genes including activating transcription factor 3 (ATF3), p21, cystathionase, dual specificity phosphatase 1 and growth differentiation factor 15, RNA interference studies demonstrated that induction of all but the later gene by DIM-C-pPhOCH(3) were TR3-dependent. We also observed that DIM-C-pPhOCH(3) induced Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and induction of TRAIL was ATF3 dependent. Results of this and previous studies demonstrate that TR3 is unique among nuclear receptors since nuclear TR3 is activated or deactivated by diindolylmethane derivatives to induce different apoptotic and growth inhibitory pathways that inhibit pancreatic cancer cell and tumor growth.
| S-EPMC3106434 | biostudies-literature
Project description:NR4A1 (Nur77, TR3) is an orphan nuclear receptor that is overexpressed in pancreatic cancer cells and tumors and exhibits pro-oncogenic activity. Knockdown of NR4A1 by RNA interference (siNR4A1) in Panc1 cells and analysis of the proteome resulted in induction of several markers of endoplasmic reticulum (ER) stress including glucose-related protein 78 (GRP78), CCAAT/enhancer-binding protein-homologous protein (CHOP), activating transcription factor-3 (ATF-3) and AFT-6. These effects were accompanied by induction of apoptosis and similar results were observed after treatment of pancreatic cancer cells with the known inactivator of NR4A1, 1,1-bis(3’-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH). Both siNR4A1 (transfected) and DIM-C-pPhOH also induced reactive oxygen species (ROS) and induction of ROS and ER stress by these agents was attenuated after cotreatment with antioxidants. Transfection of Panc1 cells with siNR4A1 follow by analysis of gene expression by arrays identified ROS metabolism genes regulated by NR4A1. Knockdown of one of these genes, thioredoxin domain containing 5 (TXNDC5) also resulted in induction of ROS and ER stress demonstrating that NR4A1 regulates levels of ER stress and ROS in pancreatic cancer cells to facilitate cell proliferation and survival. Inactivation of this receptor by siNR4A1 or DIM-C-pPhOH decreases TXNDC5 resulting in activation of ROS/ER stress and pro-apoptotic pathways and represents a novel pathway for inducing cell death in pancreatic cancer cells. Two groups of samples are included: 1. siControl; 2. siNR4A1 treatment in PAC1 cell. Transfection of Panc1 cells with siNR4A1 follow by analysis of gene expression by arrays identified ROS metabolism genes regulated by NR4A1.
2014-04-30 | E-GEOD-46994 | biostudies-arrayexpress
Project description:NR4A1 acts as an oncogene and plays an important role in colorectal cancer development and progression, but little is known about the regulatory mechanism of NR4A1 expression. MicroRNA (miRNA) is involved in the progression of various tumors, affecting proliferation, apoptosis or migration. We aimed to elucidate whether miRNA regulates NR4A1 expression and determine its underlying significance in colorectal cancer. By using the TargetScan database, we identified a miR-506 binding site in the NR4A1 3'-UTR. Examination of colorectal cancer tissues and cells revealed that NR4A1 mRNA and protein were up-regulated, while miR-506 expression was down-regulated. Spearman correlation analysis revealed that expression of NR4A1 mRNA was negatively correlated with miR-506 levels in colorectal cancer tissue. Further studies indicated that miR-506 decreased NR4A1 expression through directly targeting the NR4A1 mRNA 3'-UTR. Functional experiments showed that rescue of NR4A1 expression in cells reversed the inhibitory effects of miR-506 on proliferation, migration and invasion of colorectal cancer cells. In conclusion, miR-506 acts as a tumor suppressor and inhibits proliferation, migration and invasion in colorectal cancer cells partly through decreasing NR4A1 expression.
| S-EPMC6603418 | biostudies-literature
Project description:It was recently reported that the hydroxyflavones quercetin and kaempferol bind the orphan nuclear receptor 4A1 (NR4A1, Nur77) and act as antagonists in cancer cells and tumors, and they inhibit pro-oncogenic NR4A1-regulated genes and pathways. In this study, we investigated the interactions of flavone, six hydroxyflavones, seven dihydroxyflavones, three trihydroxyflavones, two tetrahydroxyflavones, and one pentahydroxyflavone with the ligand-binding domain (LBD) of NR4A1 using direct-binding fluorescence and an isothermal titration calorimetry (ITC) assays. Flavone and the hydroxyflavones bound NR4A1, and their KD values ranged from 0.36 µM for 3,5,7-trihydroxyflavone (galangin) to 45.8 µM for 3'-hydroxyflavone. KD values determined using ITC and KD values for most (15/20) of the hydroxyflavones were decreased compared to those obtained using the fluorescence assay. The results of binding, transactivation and receptor-ligand modeling assays showed that KD values, transactivation data and docking scores for these compounds are highly variable with respect to the number and position of the hydroxyl groups on the flavone backbone structure, suggesting that hydroxyflavones are selective NR4A1 modulators. Nevertheless, the data show that hydroxyflavone-based neutraceuticals are NR4A1 ligands and that some of these compounds can now be repurposed and used to target sub-populations of patients that overexpress NR4A1.
| S-EPMC10179475 | biostudies-literature
Project description:NR4A1 (Nur77, TR3) is an orphan nuclear receptor that is overexpressed in pancreatic cancer cells and tumors and exhibits pro-oncogenic activity. Knockdown of NR4A1 by RNA interference (siNR4A1) in Panc1 cells and analysis of the proteome resulted in induction of several markers of endoplasmic reticulum (ER) stress including glucose-related protein 78 (GRP78), CCAAT/enhancer-binding protein-homologous protein (CHOP), activating transcription factor-3 (ATF-3) and AFT-6. These effects were accompanied by induction of apoptosis and similar results were observed after treatment of pancreatic cancer cells with the known inactivator of NR4A1, 1,1-bis(3’-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH). Both siNR4A1 (transfected) and DIM-C-pPhOH also induced reactive oxygen species (ROS) and induction of ROS and ER stress by these agents was attenuated after cotreatment with antioxidants. Transfection of Panc1 cells with siNR4A1 follow by analysis of gene expression by arrays identified ROS metabolism genes regulated by NR4A1. Knockdown of one of these genes, thioredoxin domain containing 5 (TXNDC5) also resulted in induction of ROS and ER stress demonstrating that NR4A1 regulates levels of ER stress and ROS in pancreatic cancer cells to facilitate cell proliferation and survival. Inactivation of this receptor by siNR4A1 or DIM-C-pPhOH decreases TXNDC5 resulting in activation of ROS/ER stress and pro-apoptotic pathways and represents a novel pathway for inducing cell death in pancreatic cancer cells.
2014-04-30 | GSE46994 | GEO