Potent inhibition of breast cancer by bis-indole-derived nuclear receptor 4A1 (NR4A1) antagonists

Hedrick, Erik; Li, Xi; Cheng, Yueming; Lacey, Alexandra; Mohankumar, Kumaravel; Zarei, Mahsa; Safe, Stephen

doi:10.1007/s10549-019-05279-9

Cited by 23 publications

(53 citation statements)

References 30 publications

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“…The NR4A1 gene is associated with steroid hormone synthesis control (Maxwell & Muscat, 2006) and significantly inhibits the growth and proliferation of breast cancer cells (Hedrick et al, 2019). These known functions are consistent with our conclusion on the effects of DON.…”

Section: Discussionsupporting

confidence: 90%

“…Other significant DEGs identified in this study include the ITGA8 and IRF1 genes, which are related to immune response activities (Lu, Wan, Zhang, Shi, & Ye, ; Yarilina, Park‐Min, Antoniv, Hu, & Ivashkiv, ). The NR4A1 gene is associated with steroid hormone synthesis control (Maxwell & Muscat, ) and significantly inhibits the growth and proliferation of breast cancer cells (Hedrick et al, ). These known functions are consistent with our conclusion on the effects of DON.…”

Section: Discussionmentioning

confidence: 99%

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Transcriptional analysis of deoxynivalenol‐induced apoptosis of sow ovarian granulosa cell

Yang

Wang

Zhang

et al. 2020

Reprod Domestic Animals

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Litter size is one of the most important economic traits in pig production. Recent studies identified that deoxynivalenol (DON), a widespread toxin in fodder, was associated with animal prolificacy. However, the underlying mechanisms have not yet been completely elucidated. Here, we used porcine ovary granulosa cells (pGCs) as a vector to establish DON concentration–time models and performed cell morphology and transcriptome analysis to identify and analyse the effects of DON on reproductive performance in swine. The results showed that DON can induce morphological changes and apoptosis of pGCs, while inhibiting cell proliferation. Moreover, these effects of DON on pGCs were dose‐dependent. After treatment of pGCs with different concentrations of DON, the percentage of cells in S phase and G2/M phase increased. RNA‐seq analyses revealed 5,937 differentially expressed genes, of which 1995 were down‐regulated and 3,942 were up‐regulated after DON treatment. KEGG enrichment analysis indicated important metabolic pathways such as IL‐17 signalling pathway, eukaryotic ribosome synthesis pathway, RNA transport pathway and RNA degradation. Based on our results, we speculate that the effects of DON are related to the DNA damage process. Our study provides novel insights and a foundation to further understand the effect of DON on swine prolificacy.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Transcriptional analysis of deoxynivalenol‐induced apoptosis of sow ovarian granulosa cell

Yang

Wang

Zhang

et al. 2020

Reprod Domestic Animals

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“…We have also identified a series of bis-indole-derived ligands including 1,1-bis(3 0 -indolyl)-1-(p-hydroxyphenyl) methane (DIM-C-pPhOH, CDIM-8), which binds NR4A1 (K d ¼ 100 nmol/L; ref. 14) and acts as an antagonist inhibiting pro-oncogenic NR4A1-regulated pathways and genes in cancer cells (14)(15)(16)(17)(18)(19)(20)(21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

A Bis-Indole–Derived NR4A1 Antagonist Induces PD-L1 Degradation and Enhances Antitumor Immunity

et al. 2020

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PD-L1 is expressed in tumor cells and its interaction with PD-1 plays an important role in evading immune surveillance; this can be overcome using PD-L1 or PD-1 immunotherapy antibodies. This study reports a novel approach for targeting PD-L1. In human breast cancer cell lines and 4T1 mouse mammary tumor cells, PD-L1 expression was regulated by the nuclear receptor NR4A1/Sp1 complex bound to the proximal germinal center (GC)-rich region of the PD-L1 gene promoter. Treatment of breast cancer cells with bis-indole-derived NR4A1 antagonists including 1,1-bis(3 0indolyl)-1-(3-chloro-4-hydroxy-5-methoxyphenyl)methane (Cl-OCH3) decreased expression of PD-L1 mRNA, promoterdependent luciferase activity, and protein. In in vivo studies using a syngeneic mouse model bearing orthotopically injected 4T1 cells, Cl-OCH3 decreased tumor growth and weight and inhibited lung metastasis. Cl-OCH3 also decreased expression of CD3 þ /CD4 þ / CD25 þ /FoxP3 þ regulatory T cells and increased the Teff/Treg ratio. Therefore, the potent anticancer activities of NR4A1 antagonists are also accompanied by enhanced antitumor immunity in PD-L1-expressing triple-negative breast cancer and thus represent a novel class of drugs that mimic immunotherapy.Significance: These findings show that the orphan nuclear receptor NR4A1 controls PD-L1 expression and identify a chemical probe capable of disrupting this regulatory axis.

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“…Furthermore, human MZB-like cells express high levels of NR4A1 20 and PDL1, 5 and, therefore, we speculate that NR4A1 may have a similar role in human B cells, although further studies are required to determine whether this is indeed the case. The potential use of Bis-Indole-NR4A1 antagonists as anticancer treatments is starting to emerge, 18 , 21 and, therefore, we would advise to take into consideration their effect on B cells to avoid or monitor potential undesirable cardiovascular side effects associated to anticancer treatments.…”

Section: Discussionmentioning

confidence: 99%

NR4A1 Deletion in Marginal Zone B Cells Exacerbates Atherosclerosis in Mice—Brief Report

Nus

Basatemur

Galán

et al. 2020

ATVB

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Objective: NR4A orphan receptors have been well studied in vascular and myeloid cells where they play important roles in the regulation of inflammation in atherosclerosis. NR4A1 is among the most highly induced transcription factors in B cells following BCR (B-cell receptor) stimulation. Given that B cells substantially contribute to the development of atherosclerosis, we examined whether NR4A1 regulates B-cell function during atherogenesis. Approach and Results: We found that feeding Ldlr −/− mice a Western diet substantially increased Nr4a1 expression in marginal zone B (MZB) cells compared with follicular B cells. We then generated Ldlr −/− mice with complete B- or specific MZB-cell deletion of Nr4a1 . Complete B-cell deletion of Nr4a1 led to increased atherosclerosis, which was accompanied by increased T follicular helper cell–germinal center axis response, as well as increased serum total cholesterol and triglycerides levels. Interestingly, specific MZB-cell deletion of Nr4a1 increased atherosclerosis in association with an increased T follicular helper–germinal center response but without any impact on serum cholesterol or triglyceride levels. Nr4a1 −/− MZB cells showed decreased PDL1 expression, which may have contributed to the enhanced T follicular helper response. Conclusions: Our findings reveal a previously unsuspected role for NR4A1 in the atheroprotective role of MZB cells.

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Potent inhibition of breast cancer by bis-indole-derived nuclear receptor 4A1 (NR4A1) antagonists

Cited by 23 publications

References 30 publications

Transcriptional analysis of deoxynivalenol‐induced apoptosis of sow ovarian granulosa cell

Transcriptional analysis of deoxynivalenol‐induced apoptosis of sow ovarian granulosa cell

A Bis-Indole–Derived NR4A1 Antagonist Induces PD-L1 Degradation and Enhances Antitumor Immunity

NR4A1 Deletion in Marginal Zone B Cells Exacerbates Atherosclerosis in Mice—Brief Report

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