Nuclear Receptor 4A1 (NR4A1) as a Drug Target for Renal Cell Adenocarcinoma

Hedrick, Erik; Lee, Syng‐Ook; Kim, Gyungeun; Abdelrahim, Maen; Jin, Un Ho; Safe, Stephen; Abudayyeh, Ala

doi:10.1371/journal.pone.0128308

Cited by 54 publications

(88 citation statements)

References 41 publications

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“…Similar results were observed after treatment with DIM-C-pPhCO 2 Me. We also recently observed similar results in a p53-mutant renal adenocarcinoma cell line (Hedrick et al 2015) which showed that induction of SESN2 was ROS-dependent. This was consistent with previous reports showing that SESN2 was an oxygen-sensing gene (Budanov et al 2002).…”

Section: Sinr4a1 and Dim-c-pphco 2 Me Inhibit Mtor Signalingsupporting

confidence: 76%

Nuclear receptor 4A1 as a drug target for breast cancer chemotherapy

Hedrick¹,

Lee²,

Doddapaneni³

et al. 2015

Endocrine-Related Cancer

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The orphan nuclear receptor 4A1 (NR4A1) is overexpressed in mammary tumors and breast cancer cell lines. The functional activity of this receptor was investigated by RNA interference with oligonucleotides targeted to NR4A1 (siNR4A1) and by treatment with NR4A1 antagonists. Breast cancer cells were treated with NR4A1 antagonists or transfected with siNR4A. Effects on cell proliferation and apoptosis as well as specific genes associated with these responses were investigated in MCF-7, SKBR3, and MDA-MB-231 cells, and in athymic nude mice bearing MDA-MB-231 cells as xenografts. Transfection of MCF-7, MDA-MB-231, and SKBR3 breast cancer cells with siNR4A1 decreased cell proliferation and induced apoptosis in these cell lines. Transfection of breast cancer cells with siNR4A1 also decreased expression of Sp-regulated genes including survivin, bcl-2, and epidermal growth factor receptor, inhibited mTOR signaling in MCF-7 cells that express WT p53, and activated oxidative and endoplasmic reticulum stress through downregulation of thioredoxin domain-containing 5 and isocitrate dehydrogenase 1. 1,1-Bis(3 0 -indolyl)-1-(p-substituted phenyl)methanes (C-DIMs) are NR4A1 ligands that act as NR4A1 antagonists. Treatment with selected analogs also inhibited breast cancer cell and tumor growth and induced apoptosis.The effects of C-DIM/NR4A1 antagonists were comparable to those observed after NR4A1 knockdown. Results with siNR4A1 or C-DIMs/NR4A1 antagonists in breast cancer cells and tumors were similar to those previously reported in pancreatic, lung, and colon cancer cells. They demonstrate the potential clinical applications of NR4A1 antagonists in patients with tumors that overexpress this receptor.

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Section: Sinr4a1 and Dim-c-pphco 2 Me Inhibit Mtor Signalingsupporting

confidence: 76%

Nuclear receptor 4A1 as a drug target for breast cancer chemotherapy

Hedrick¹,

Lee²,

Doddapaneni³

et al. 2015

Endocrine-Related Cancer

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“…The cells were visualized by microscopy (Advanced Microscopy), and NR4A1 localization was determined by green fluorescence. DAPI was used to stain the nucleus, and images were taken sequentially of NR4A1, DAPI, and then merged (28)(29)(30).…”

Section: Methodsmentioning

confidence: 99%

“…SKBR3, MDA-MB-231, and MCF-7 cancer cells (3.0 ϫ 10 5 per well) were seeded in Dulbecco's modified Eagle's medium-Ham's F-12 medium supplemented with 2.5% charcoalstripped fetal bovine serum and were allowed to attach for 24 h. The cells were transfected with 100 nM si␤1-integrin, siNR4A1, siSp1, or sip300 for 72 h or treated with various C-DIM compounds. Cell lysates were analyzed by Western blotting as described previously (28)(29)(30).…”

Section: Methodsmentioning

confidence: 99%

“…Small interfering RNA (siRNA) experiments were conducted as described previously (28)(29)(30). The siRNA complexes used in the study are as follows: siGL2-5=, CGU ACG CGG AAU ACU UCG A; siNR4A1, SASI_Hs02_00333289 [1], SASI_Hs02_00333290 [2]; si␤1-integrin, SASI_Hs02_00333437 [1], SASI_Hs01_00159474; siSp1, SASI_Hs02_003; sip300, SASI_Hs01_ 00052818.…”

Section: Methodsmentioning

confidence: 99%

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NR4A1 Antagonists Inhibit β1-Integrin-Dependent Breast Cancer Cell Migration

Hedrick

Lee

Doddapaneni

et al. 2016

Molecular and Cellular Biology

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cOverexpression of the nuclear receptor 4A1 (NR4A1) in breast cancer patients is a prognostic factor for decreased survival and increased metastasis, and this has been linked to NR4A1-dependent regulation of transforming growth factor ␤ (TGF-␤) signaling. Results of RNA interference studies demonstrate that basal migration of aggressive SKBR3 and MDA-MB-231 breast cancer cells is TGF-␤ independent and dependent on regulation of ␤1-integrin gene expression by NR4A1 which can be inhibited by the NR4A1 antagonists 1,1-bis(3=-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) and a related p-carboxymethylphenyl [1,1-bis(3=-indolyl)-1-(p-carboxymethylphenyl)methane (DIM-C-pPhCO 2 Me)] analog. The NR4A1 antagonists also inhibited TGF-␤-induced migration of MDA-MB-231 cells by blocking nuclear export of NR4A1, which is an essential step in TGF-␤-induced cell migration. We also observed that NR4A1 regulates expression of both ␤1-and ␤3-integrins, and unlike other ␤1-integrin inhibitors which induce prometastatic ␤3-integrin, NR4A1 antagonists inhibit expression of both ␤1-and ␤3-integrin, demonstrating a novel mechanism-based approach for targeting integrins and integrin-dependent breast cancer metastasis. Cell adhesion and attachment are essential for tissue integrity and cellular homeostasis, and the heterodimeric integrin cell surface receptors play a critical role in these processes (1-3). There are 18 different ␣ subunits and 8 different ␤ subunits that form 24 ␣␤-integrin receptor heterodimers, and the large 12-member ␤1-integrin subgroup bind multiple extracellular matrix (ECM) molecules to activate multiple intracellular pathways and also induce cross talk with other signaling systems (1-3). The functions of integrin heterodimers are highly tissue specific, and many human pathologies also involve integrin signaling (reviewed in references 4 and 5). ␤1-Integrin is highly expressed in most tumors and is associated with a negative prognostic significance such as overall and disease-free survival, recurrence, and metastasis for head and neck and squamous cell carcinoma, melanoma, lung, breast, prostate, laryngeal, and pancreatic cancers (6-17). A recent immunostaining study of 225 breast invasive ductal carcinomas (IDCs) showed that ␤1-integrin was overexpressed in 32.8% of patients with IDCs (13). Numerous studies show that focal adhesion kinase (FAK) which is downstream from ␤1-integrin is also a negative prognostic factor for breast cancer patients (18)(19)(20). The important functional role of ␤1-integrin has been demonstrated in mouse models expressing erbB2 under the control of the mouse mammary tumor virus and crossed with mammary tissue-specific ␤1-integrin-deficient mice. These mice exhibit a decrease in tumor volume, increased apoptosis, and decreased lung metastasis compared to animals expressing wild-type ␤1-integrin (21-23). Although small molecules, peptides, and antibodies that inhibit ␤1-integrin signaling have been developed, clinical agents that target ␤1-integrin for cancer chemotherapy are not cur...

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“…Intriguingly, some selected compounds in the series of DIM analogs, such as DIM-C-pPhO, DIM-C-pPhOH and DIM-CpPhCO 2 Me, act as NGFI-B antagonists. These compounds can induce apoptosis and inhibit tumor growth of cancers, such as pancreatic [84], lung [85], colon [86], breast cancer cells [81] and renal cell adenocarcinoma [87], where NGFI-B is overexpressed, via targeting and suppression of NGFI-B-mediated pro-oncogenic pathways. NGFI-B is shown to promote breast cancer invasion and metastasis by activating TGF-β/SMAD signaling [88] and NGFI-B antagonists can significantly suppress TGF-β-induced migration of breast cancer cells [89].…”

Section: Ngfi-bsmentioning

confidence: 99%

The emerging roles of orphan nuclear receptors in prostate cancer

Cheung

Wang

et al. 2016

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Orphan nuclear receptors are members of the nuclear receptor (NR) superfamily and are so named because their endogenous physiological ligands are either unknown or may not exist. Because of their important regulatory roles in many key physiological processes, dysregulation of signalings controlled by these receptors is associated with many diseases including cancer. Over years, studies of orphan NRs have become an area of great interest because their specific physiological and pathological roles have not been well-defined, and some of them are promising drug targets for diseases. The recently identified synthetic small molecule ligands, acting as agonists or antagonists, to these orphan NRs not only help to understand better their functional roles but also highlight that the signalings mediated by these ligand-independent NRs in diseases could be therapeutically intervened. This review is a summary of the recent advances in elucidating the emerging functional roles of orphan NRs in cancers, especially prostate cancer. In particular, some orphan NRs, RORγ, TR2, TR4, COUP-IFII, ERRα, DAX1 and SHP, exhibit crosstalk or interference with androgen receptor (AR) signaling in either normal or malignant prostatic cells, highlighting their involvement in prostate cancer progression as androgen and AR signaling pathway play critical roles in this process. We also propose that a better understanding of the mechanism of actions of these orphan NRs in prostate gland or prostate cancer could help to evaluate their potential value as therapeutic targets for prostate cancer.

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Nuclear Receptor 4A1 (NR4A1) as a Drug Target for Renal Cell Adenocarcinoma

Cited by 54 publications

References 41 publications

Nuclear receptor 4A1 as a drug target for breast cancer chemotherapy

Nuclear receptor 4A1 as a drug target for breast cancer chemotherapy

NR4A1 Antagonists Inhibit β1-Integrin-Dependent Breast Cancer Cell Migration

The emerging roles of orphan nuclear receptors in prostate cancer

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