Flavone and Hydroxyflavones Are Ligands That Bind the Orphan Nuclear Receptor 4A1 (NR4A1)
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 flav...
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MDPI AG
2023-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/9/8152 |
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| author | Miok Lee Srijana Upadhyay Fuada Mariyam Greg Martin Amanuel Hailemariam Kyongbum Lee Arul Jayaraman Robert S. Chapkin Syng-Ook Lee Stephen Safe |
| author_facet | Miok Lee Srijana Upadhyay Fuada Mariyam Greg Martin Amanuel Hailemariam Kyongbum Lee Arul Jayaraman Robert S. Chapkin Syng-Ook Lee Stephen Safe |
| author_sort | Miok Lee |
| collection | DOAJ |
| 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 K<sub>D</sub> values ranged from 0.36 µM for 3,5,7-trihydroxyflavone (galangin) to 45.8 µM for 3′-hydroxyflavone. K<sub>D</sub> values determined using ITC and K<sub>D</sub> 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 K<sub>D</sub> 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. |
| first_indexed | 2024-03-11T04:16:02Z |
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| language | English |
| last_indexed | 2024-03-11T04:16:02Z |
| publishDate | 2023-05-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-45d27ba82a1c49cfaf58515359884b362023-11-17T23:05:35ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-05-01249815210.3390/ijms24098152Flavone and Hydroxyflavones Are Ligands That Bind the Orphan Nuclear Receptor 4A1 (NR4A1)Miok Lee0Srijana Upadhyay1Fuada Mariyam2Greg Martin3Amanuel Hailemariam4Kyongbum Lee5Arul Jayaraman6Robert S. Chapkin7Syng-Ook Lee8Stephen Safe9Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USADepartment of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USADepartment of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USADepartment of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USADepartment of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USADepartment of Chemical and Biological Engineering, Tufts University, Medford, MA 02155, USAArtie McFerrin Department of Chemical Engineering, Texas A&M University, College Station, TX 77843, USADepartment of Nutrition, Texas A&M University, College Station, TX 77843, USADepartment of Food Science and Technology, Keimyung University, Daegu 42601, Republic of KoreaDepartment of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USAIt 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 K<sub>D</sub> values ranged from 0.36 µM for 3,5,7-trihydroxyflavone (galangin) to 45.8 µM for 3′-hydroxyflavone. K<sub>D</sub> values determined using ITC and K<sub>D</sub> 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 K<sub>D</sub> 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.https://www.mdpi.com/1422-0067/24/9/8152flavonehydroxyflavonesbindingNR4A1 |
| spellingShingle | Miok Lee Srijana Upadhyay Fuada Mariyam Greg Martin Amanuel Hailemariam Kyongbum Lee Arul Jayaraman Robert S. Chapkin Syng-Ook Lee Stephen Safe Flavone and Hydroxyflavones Are Ligands That Bind the Orphan Nuclear Receptor 4A1 (NR4A1) International Journal of Molecular Sciences flavone hydroxyflavones binding NR4A1 |
| title | Flavone and Hydroxyflavones Are Ligands That Bind the Orphan Nuclear Receptor 4A1 (NR4A1) |
| title_full | Flavone and Hydroxyflavones Are Ligands That Bind the Orphan Nuclear Receptor 4A1 (NR4A1) |
| title_fullStr | Flavone and Hydroxyflavones Are Ligands That Bind the Orphan Nuclear Receptor 4A1 (NR4A1) |
| title_full_unstemmed | Flavone and Hydroxyflavones Are Ligands That Bind the Orphan Nuclear Receptor 4A1 (NR4A1) |
| title_short | Flavone and Hydroxyflavones Are Ligands That Bind the Orphan Nuclear Receptor 4A1 (NR4A1) |
| title_sort | flavone and hydroxyflavones are ligands that bind the orphan nuclear receptor 4a1 nr4a1 |
| topic | flavone hydroxyflavones binding NR4A1 |
| url | https://www.mdpi.com/1422-0067/24/9/8152 |
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