Resveratrol Binds Nuclear Receptor 4A1 (NR4A1) and Acts as an NR4A1 Antagonist in Lung Cancer Cells

Zhang, Lei; Martin, Greg; Mohankumar, Kumaravel; Hampton, Joshua Trae; Liu, Wenshe Rayi; Safe, Stephen

doi:10.1124/molpharm.121.000481

Cited by 9 publications

(6 citation statements)

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“…These results ( Figures 3D,E ) demonstrate that piperlongumine affects functional responses in colon cancer cells that are consistent with their activity as inverse NR4A1 agonists and effects of NR4A1 knockdown ( Safe et al, 2021 ). We also show that in contrast with results observed for bis-indole derived inverse NR4A1 agonists and resveratrol that piperlongumine did not affect expression of β1-integrin and other integrins ( Supplementary Figure S1D ) ( Zhang et al, 2022 ).…”

Section: Resultscontrasting

confidence: 61%

“…It was previously reported that the flavonoid kaempferol downregulated expression of G9a in gastric cancer cells ( Kim et al, 2018 ) and studies in this laboratory reported that the flavonoids quercetin and kaempferol bind NR4A1 and downregulate G9a and other NR4A1-regulated genes in Rh30 cells ( Shrestha et al, 2021 ) and similar results have now been observed for piperlongumine ( Figure 7 ). Several other natural products that act as anticancer agents including cytosporone B, celastrol, resveratrol and some alkaloids have also been identified as NR4A1 ligands and this will help facilitate their repurposing for treating diseases such as cancer and other inflammatory diseases in patients that highly express this receptor ( Liu et al, 2010 ; Hu et al, 2017 ; Safe et al, 2021 ; Shrestha et al, 2021 ; Zhang et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

“…Previous modeling studies showed that NR4A1 binding with structurally diverse ligands exhibited both common and different interactions with amino acid side chain within the LBD. For example, the key amino acid side chain interactions were observed for the following compounds; quercetin (Glu109, Phe112, Leu113, Glu114) [41], 1,1-bis(3′-indolyl)-1-(3,5-dichlorophenyl) methane (Ser110, Glu114, Arg184, Arg232 and Thr236) and resveratrol (Ser110, Leu113, Glu114, Arg184, Thr236, Leu239, and Ile-260) ( Zhang et al, 2022 ). Thus, these structurally-diverse ligands interact with some of the same amino acid side chains but they also exhibit some differences and this could influence their recruitment of other nuclear cofactors and contribute to their activity as selective receptor modulators.…”

Section: Discussionmentioning

confidence: 99%

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Piperlongumine is a ligand for the orphan nuclear receptor 4A1 (NR4A1)

Zhang,

Martin,

Mohankumar

et al. 2023

Front. Pharmacol.

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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.

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Section: Resultscontrasting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Piperlongumine is a ligand for the orphan nuclear receptor 4A1 (NR4A1)

Zhang,

Martin,

Mohankumar

et al. 2023

Front. Pharmacol.

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“…Recent studies show that polyphenolic compounds such as quercetin, kaempferol, broussochalcone and resveratrol bind the orphan nuclear receptor NR4A1, and in cancer cell models these compounds act as NR4A1 antagonists [33][34][35]. In this study, we examined the direct binding of flavone and structurally diverse hydroxyflavones which contained a variable number of hydroxyl groups with different substitution patterns to the ligand-binding domain of NR4A1.…”

Section: Resultsmentioning

confidence: 99%

Flavone and Hydroxyflavones Are Ligands That Bind the Orphan Nuclear Receptor 4A1 (NR4A1)

Lee

Upadhyay

Mariyam

et al. 2023

IJMS

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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.

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“…PTGS2 [196], NR4A1 [197], IL6 [198], CXCL1 [199], SOCS3 [200], CCL3 [201], CCL5 [202], CCL2 [203], NR4A2 [204], CXCL12 [205], DUSP1 [206], GADD45B [207], APLNR (apelin receptor) [208], IL1B [209], SERPINE1 [210], CCL11 [211], APLN (apelin) [212], HCAR2 [213], IFNG (interferon gamma) [214], CX3CL1 [215], LDLR (low density lipoprotein receptor) [216], TNFAIP3 [217], BMP5 [218], ITK (IL2 inducible T cell kinase) [219], ICAM1 [220], SNCA (synuclein alpha) [221], CD34 [222], HOMER1 [223], IL33 [224], CPE (carboxypeptidase E) [225], KDM6B [226], TNF (tumor necrosis factor) [227], GDF15 [228], CCL22 [229], CCR4 [230], IL2 [231], IRF1 [196], FABP4 [232], CYP2C19 [233], CXCR4 [234], TFPI2 [235], ANXA1 [236], RGS5 [237], TFF3 [238], S100A9 [239], FKBP5 [240], ARG1 [241], RASD1 [242], ADRA1A [243], STAB1 [244], ABCB6 [245], IFNGR1 [246], GPER1 [247], SLC1A3 [248], GLUL (glutamate-ammonia ligase) [249], GATA2 [250], OLFM4 [251], FADS1 [252], KL (klotho) [253], FPR2 [254], FGF22 [255], MPO (myeloperoxidase) [256], MAOA (monoamine oxidase A) [257], BRINP1 [258], CTSD (cathepsin D) [259], BAX (BCL2 associated X, apoptosis regulator) [260], FADS2 [261], EHD3 [262] and PSAT1 [263] are a major mediators of depression and anxiety. PTGS2 [264], NR4A1 [265], EGR3 [266], KLRK1 [267], IL6 […”

Section: Discussionmentioning

confidence: 99%

Identification of key genes and biological pathways in chronic obstructive pulmonary disease using bioinformatics and next generation sequencing data analysis

Vastrad,

Vastrad

2024

Preprint

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Identification of accurate biomarkers is still particularly urgent for improving the poor survival of chronic obstructive pulmonary disease (COPD) patients. In this investigation, we aimed to identity the potential biomarkers in COPD via bioinformatics and next generation sequencing (NGS) data analysis. In this investigation, the differentially expressed genes (DEGs) in COPD were identified using NGS dataset (GSE239897) from Gene Expression Omnibus (GEO) database. Subsequently, gene ontology (GO) and pathway enrichment analysis was conducted to evaluate the underlying molecular mechanisms involved in progression of COPD. Protein-protein interaction (PPI), modules, miRNA-hub gene regulatory network and TF-hub gene regulatory network analysis were performed to determine the hub genes, miRNAs and TFs. The receiver operating characteristic (ROC) analysis was performed to determine the diagnostic value of hub genes. A total of 956 overlapping DEGs (478 up regulated and 478 down regulated genes) were identified in the NGS dataset. DEGs were mainly associated with GO functional terms and pathways in cellular response to stimulus. response to stimulus, immune system and neutrophil degranulation. There were 10 hub genes (MYC, LMNA, VCAM1, MAPK6, DDX3X, SHMT2, PHGDH, S100A9, FKBP5 and RPS6KA2) identified by PPI, modules, miRNA-hub gene regulatory network and TF-hub gene regulatory network analysis. In conclusion, the DEGs, relative GO terms, pathways and hub genes identified in the present investigation might aid in understanding of the molecular mechanisms underlying COPD progression and provide potential molecular targets and biomarkers for COPD.

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Resveratrol Binds Nuclear Receptor 4A1 (NR4A1) and Acts as an NR4A1 Antagonist in Lung Cancer Cells

Cited by 9 publications

References 50 publications

Piperlongumine is a ligand for the orphan nuclear receptor 4A1 (NR4A1)

Piperlongumine is a ligand for the orphan nuclear receptor 4A1 (NR4A1)

Flavone and Hydroxyflavones Are Ligands That Bind the Orphan Nuclear Receptor 4A1 (NR4A1)

Identification of key genes and biological pathways in chronic obstructive pulmonary disease using bioinformatics and next generation sequencing data analysis

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