Orphan nuclear receptor TR3 acts in autophagic cell death via mitochondrial signaling pathway

Wang, Weijia; Wang, Yuan; Chen, Hang-zi; Xing, Yong-zhen; Li, Feng-wei; Zhang, Qian; Zhou, Bo; Zhang, Hongkui; Zhang, Jie; Bian, Xueli; Li, Li; Liu, Yuan; Zhao, Bixing; Chen, Yan; Wu, Rong; Li, Anzhong; Yao, Luming; Chen, Ping; Zhang, Yi; Tian, Xiaojuan; Beermann, Friedrich; Wu, Mian; Han, Jiahuai; Huang, Pei‐Qiang; Lin, Tianwei; Wu, Qiao

doi:10.1038/nchembio.1406

Cited by 191 publications

(126 citation statements)

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“…Cytosporone B (Csn-B), an octaketide antibiotic isolated from an endophytic fungus, and its analogs were identified a new class of antitumor agents [90][91][92]. Recently, a chemical compound THPN [1-(3,4,5-trihydroxyphenyl)nonan-1-one] was confirmed as a new NGFI-B-specific agonist, which can effectively mediate autophagic cell death and mitochondrial targeting in melanoma cells and inhibit melanoma growth [93].…”

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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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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“…Finally, recombinant adenovirus was stepwise amplified and purified by cesium chloride gradient centrifugation and concentrated to 10 12 viral particles/mL. The lentivirus system was generated as previously described (15). The knockdown efficiency was determined by Western blot or real-time PCR.…”

Section: Recombinant Adenovirus and Lentivirus Hypothalamic Injectionmentioning

confidence: 99%

Enhancement of Hypothalamic STAT3 Acetylation by Nuclear Receptor Nur77 Dictates Leptin Sensitivity

Chen

et al. 2015

Diabetes

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Leptin, an anorexigenic hormone in the hypothalamus, suppresses food intake and increases energy expenditure. Failure to respond to leptin will lead to obesity. Here, we discovered that nuclear receptor Nur77 expression is lower in the hypothalamus of obese mice compared with normal mice. Injection of leptin results in significant reduction in body weight in wild-type mice but not in Nur77 knockout (KO) littermates or mice with specific Nur77 knockdown in the hypothalamus. Hypothalamic Nur77 not only participates in leptin central control of food intake but also expands leptin's reach to liver and adipose tissues to regulate lipid metabolism. Nur77 facilitates signal transducer and activator of transcription 3 (STAT3) acetylation by recruiting acetylase p300 and disassociating deacetylase histone deacetylase 1 (HDAC1) to enhance the transcriptional activity of STAT3 and consequently modulates the expression of downstream gene Pomc in the hypothalamus. Nur77 deficiency compromises response to leptin in mice fed a high-fat diet. Severe leptin resistance in Nur77 KO mice with increased appetite, lower energy expenditure, and hyperleptinemia contributes to aginginduced obesity. Our study opens a new avenue for regulating metabolism with Nur77 as the positive modulator in the leptin-driven antiobesity in the hypothalamus.The hypothalamus is the major center for regulating energy homeostasis by sensing and responding to input from hormonal and nutrient-related signals (1). Among various signals sensed by the hypothalamus, leptin is an important hormone derived from adipocytes with a key role in representing nutritional status to the hypothalamus for the regulation of energy balance (2). This regulation is mostly mediated by several well-structured nuclei in the hypothalamus, especially in arcuate nucleus (ARC) (3). Two distinct populations of neurons in ARC, proopiomelanocortin (Pomc) neurons and agouti-related protein (AgRp) neurons, are regulated by leptin in completely different fashions. Leptin suppresses the expression of orexigenic neuropeptide AgRp and neuropeptide Y (NPY) in AgRp neurons but upregulates the expression of anorexigenic neuropeptide Pomc in Pomc neurons (3). Leptin's function in these neurons is critical to normal food intake and body weight, and its dysregulation would break energy homeostasis. Leptin signaling ablation from the mutations of db or ob genes in mice would result in severe obesity and diabetes (4). Administration of leptin greatly reduces body weight and food intake in normal mice but not in obese mice. This phenomenon, together with higher circulating leptin level in the obese, is the so-called leptin resistance.Signal transducer and activator of transcription 3 (STAT3) is an important downstream component in leptin signaling on energy balance for the regulation of body weight and food intake (5). Mouse models with neural deletion of STAT3 develop hyperphagia and obesity, as well as severe diabetes (6). As Tyr 1138 of OB-Rb (the long form of leptin receptor) is specific for STAT3 ...

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“…This has led to the development of peptide mimics that convert bcl-2 into an apoptotic complex; similar results have been reported for the taxane-derived anticancer agent paclitaxel (Kolluri et al 2008, Ferlini et al 2009). Cytosporone B and related analogs have been identified as ligands for NR4A1 (Zhan et al 2008, Liu et al 2010, and two additional compounds, (ethyl 2-(2,3,4-trimethoxy-6-(1-octanoyl)phenyl)acetate and 1-(3,4,5-trihydroxyphenyl) no-nan-1-one), also bind NR4A1 (Zhan et al 2012, Wang et al 2014. Ethyl 2-(2,3,4-trimethoxy-6-(1-oct-anoyl) phenyl)acetate inactivates nuclear NR4A1, whereas 1-(3,4,5-trihydroxyphenyl)no-nan-1-one and cytosporone B induce nuclear export of NR4A1.…”

Section: Introductionmentioning

confidence: 99%

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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Orphan nuclear receptor TR3 acts in autophagic cell death via mitochondrial signaling pathway

Cited by 191 publications

References 50 publications

The emerging roles of orphan nuclear receptors in prostate cancer

The emerging roles of orphan nuclear receptors in prostate cancer

Enhancement of Hypothalamic STAT3 Acetylation by Nuclear Receptor Nur77 Dictates Leptin Sensitivity

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

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