Orphan nuclear receptor TR3/Nur77 biologics inhibit tumor growth by targeting angiogenesis and tumor cells

Chen, Chen; Li, Yan; Hou, Shiqiang; Bourbon, Pierre M.; Qin, LiuLiang; Zhao, Kevin T.; Ye, Taiyang; Zhao, Dan; Zeng, Hui

doi:10.1016/j.mvr.2019.103934

Cited by 15 publications

(8 citation statements)

References 26 publications

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“…Other potential targets revealed during the in silico “target fishing” reverse screening, including Poly(ADP-ribose)polymerase (PARP), 82, 83 phosphodiesterase type 5, 84, 85 orphan nuclear receptor LRH-1, 86, 87 nuclear receptor ROR-gamma, 88, 89 matrix metallopeptidase 9 (MMP9), 90 NAD-dependent deacetylase Sirtuin 2, 91 and cholesterol ester transfer protein, 92 all believed to play important roles in skin carcinogenesis. There is no doubt that the wealth of information gathered here will be useful in further studies towards the optimizing the hit molecules’ activity and determining their putative drug target and potential mechanism(s) of action.…”

Section: Resultsmentioning

confidence: 99%

Identification of potential inhibitors of cutaneous Melanoma and Non-Melanoma skin cancer cells through in-vitro and in-silico screening of a small library of Phenolic compounds

Boateng

Roy

Agbo

et al. 2022

Preprint

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Melanoma and nonmelanoma skin cancer are the most lethal and commonest forms of skin cancers affecting one fifth of the US population. With the aim of identifying new lead compounds as starting point for attaining cost effective therapies, a small library of about 90 molecules was screened in vitro against A375, SKMEL28, A431, SCC12 skin cancer cell lines. About 35 of them, mainly dihydroquinolines, CC and CN linked biphenyls, and substituted methyl gallate or aniline derivatives, displayed low micromolar range activities, primarily against the A431 and SCC12 squamous carcinoma cell lines, with only a handful of these compounds displaying any activity against the A375 and SKMEL28 melanoma cell lines. Compounds 11 (A431: IC50 = 5.0 lower case Greek muM, SCC12: IC50 = 2.9 lower case Greek muM, SKMEL-28: IC50 = 4.9 lower case Greek muM, A375: IC50 = 6.7 lower case Greek muM) and 13 (A431: IC50 = 5.0 lower case Greek muM, SCC-12: IC50 = 3.3 lower case Greek muM, SKMEL-28: IC50 = 13.8 lower case Greek muM, A375: IC50 = 17.1 lower case Greek muM) were the most active across all these cell lines. Furthermore, many of the hit compounds showed little to no activity against mammalian nontumorigenic immortalized HaCaT cells, with a far better selectivity index than cisplatin (a well-known anticancer agent used as a positive control). Compounds 11 and 13 significantly and dose dependently induced apoptosis of SCC12 and SKMEL28 cells as evidenced by the downregulation of Bcl2 and upregulation of Bax protein expression levels, and by cleaved caspase 3, caspase 9 and PARP levels. Both agents also significantly reduced scratch wound healing, colony formation, and activated expression levels of major cancer molecular targets such as RSK/AKT/ERK1/2 and S6K1. To provide a better attribute profile for each of the hit molecules, in silico target(s) prediction, pharmacokinetic and ADMET studies are also reported, together with some preliminary structure activity relationship outlines. The SwissTargetPrediction web-based tool identified CDK8, CLK4, nuclear receptor ROR, tyrosine protein-kinase Fyn/LCK, ROCK1/2, and PARP, all of which are dysregulated in skin cancers, as likely targets for these hit compounds. Furthermore, the SwissADME web_tool predicted these compounds to exhibit high GI tract absorption, good skin permeation, and a viable biodegradability profile. To summarize, these data highlight the promising anticancer potential of these small molecules leads, warranting further investigation and/or optimization towards obtaining clinical candidates for combatting both melanoma and nonmelanoma skin cancers.

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Section: Resultsmentioning

confidence: 99%

Identification of potential inhibitors of cutaneous Melanoma and Non-Melanoma skin cancer cells through in-vitro and in-silico screening of a small library of Phenolic compounds

Boateng

Roy

Agbo

et al. 2022

Preprint

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“…In the present study, NR4A1 was found to be the main target gene of circSCRG1 and the therapeutic target of TMP-PF in the regulation of angiogenesis in atherosclerosis. A previous study showed that NR4A1 was a critical transcription factor in VEGF pathway-mediated angiogenesis, and NR4A1 silencing could significantly inhibit VEGF-induced angiogenesis [ 37 ]. Previous studies have primarily focused on the bidirectional roles of NR4A1 in the inflammatory response of atherosclerosis [ 38 ] or NR4A1-mediated pro-angiogenic effects in tumour growth and skin wound healing [ 39 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of a Novel Angiogenesis Signalling circSCRG1/miR-1268b/NR4A1 Pathway in Atherosclerosis and the Regulatory Effects of TMP-PF In Vitro

Yuan

Xin

et al. 2023

Molecules

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Angiogenesis contributes to plaque instability in atherosclerosis and further increases cardio-cerebrovascular risk. Circular RNAs (circRNAs) are promising biomarkers and potential therapeutic targets for atherosclerosis. Previous studies have demonstrated that tetramethylpyrazine (TMP) and paeoniflorin (PF) combination treatment (TMP-PF) inhibited oxidized low-density lipoprotein (ox-LDL)-induced angiogenesis in vitro. However, whether circRNAs regulate angiogenesis in atherosclerosis and whether TMP-PF can regulate angiogenesis-related target circRNAs in atherosclerosis are unknown. In this study, human RNA sequencing (RNA-seq) data were analysed to identify differentially expressed (DE) circRNAs in atherosclerosis and to obtain angiogenesis-associated circRNA-microRNA (miRNA)-messenger RNA (mRNA) networks. Target circRNA-related mechanisms in angiogenesis in atherosclerosis and the regulatory effects of TMP-PF on target circRNA signalling were studied in ox-LDL-induced human umbilical vein endothelial cells (HUVECs) by cell proliferation, migration, tube formation, and luciferase reporter assays, real-time quantitative polymerase chain reaction (RT-qPCR) and Western blotting. A novel circRNA (circular stimulator of chondrogenesis 1, circSCRG1) was initially identified associated with angiogenesis in atherosclerosis, and circSCRG1 silencing up-regulated miR-1268b expression, increased nuclear receptor subfamily 4 group A member 1 (NR4A1) expression and then promoted ox-LDL-induced angiogenesis. TMP-PF (1 μmol/L TMP combined with 10 μmol/L PF) up-regulated circSCRG1 expression, mediated miR-1268b to suppress NR4A1 expression and then inhibited ox-LDL-induced angiogenesis. However, circSCRG1 silencing abolished the inhibitory effects of TMP-PF on ox-LDL-induced angiogenesis, which were rescued by the miR-1268b inhibitor. In conclusion, circSCRG1 might serve as a new target regulating angiogenesis in atherosclerosis via the circSCRG1/miR-1268b/NR4A1 axis and TMP-PF could regulate the circSCRG1/miR-1268b/NR4A1 axis to inhibit angiogenesis in atherosclerosis in vitro, indicating a novel angiogenesis signalling circSCRG1/miR-1268b/NR4A1 pathway in atherosclerosis and the regulatory effects of TMP-PF, which might provide a new pharmaceutical strategy to combat atherosclerotic plaque instability.

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“…NR4A1 is a well-studied transcription factor, and recent researches focus on identifying its genomic and non-genomic effects in cancers, including melanoma ( 106 ), breast cancer ( 107 ), and colorectal cancer ( 31 ). As described above, NR4A1 exhibits important functions in cancer cell metabolic reprogramming.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic potential of NR4A1 in cancer: Focus on metabolism

et al. 2022

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Metabolic reprogramming is a vital hallmark of cancer, and it provides the necessary energy and biological materials to support the continuous proliferation and survival of tumor cells. NR4A1 is belonging to nuclear subfamily 4 (NR4A) receptors. NR4A1 plays diverse roles in many tumors, including melanoma, colorectal cancer, breast cancer, and hepatocellular cancer, to regulate cell growth, apoptosis, metastasis. Recent reports shown that NR4A1 exhibits unique metabolic regulating effects in cancers. This receptor was first found to mediate glycolysis via key enzymes glucose transporters (GLUTs), hexokinase 2 (HK2), fructose phosphate kinase (PFK), and pyruvate kinase (PK). Then its functions extended to fatty acid synthesis by modulating CD36, fatty acid-binding proteins (FABPs), sterol regulatory element-binding protein 1 (SREBP1), glutamine by Myc, mammalian target of rapamycin (mTOR), and hypoxia-inducible factors alpha (HIF-1α), respectively. In addition, NR4A1 is involving in amino acid metabolism and tumor immunity by metabolic processes. More and more NR4A1 ligands are found to participate in tumor metabolic reprogramming, suggesting that regulating NR4A1 by novel ligands is a promising approach to alter metabolism signaling pathways in cancer therapy. Basic on this, this review highlighted the diverse metabolic roles of NR4A1 in cancers, which provides vital references for the clinical application.

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Orphan nuclear receptor TR3/Nur77 biologics inhibit tumor growth by targeting angiogenesis and tumor cells

Cited by 15 publications

References 26 publications

Identification of potential inhibitors of cutaneous Melanoma and Non-Melanoma skin cancer cells through in-vitro and in-silico screening of a small library of Phenolic compounds

Identification of potential inhibitors of cutaneous Melanoma and Non-Melanoma skin cancer cells through in-vitro and in-silico screening of a small library of Phenolic compounds

Identification of a Novel Angiogenesis Signalling circSCRG1/miR-1268b/NR4A1 Pathway in Atherosclerosis and the Regulatory Effects of TMP-PF In Vitro

Therapeutic potential of NR4A1 in cancer: Focus on metabolism

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