Identification of a Chemical Tool for the Orphan Nuclear Receptor FXR

Maloney, Patrick; Parks, Derek J.; Haffner, Curt D.; Fivush, Adam M.; Chandra, Gyan; Plunket, Kelli D.; Creech, Katrina L.; Moore, Linda B.; Wilson, Joan G.; Lewis, Michael C.; Jones, Stacey A.; Willson, Timothy M.

doi:10.1021/jm0002127

Cited by 497 publications

(375 citation statements)

References 20 publications

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“…IC50 values were determined for all conditions and are presented in Table 1. We note that, as expected, IC50 values for GW4064 are approximately three orders of magnitude lower than for CDCA, consistent with the higher affinity of this ligand for FXR [GW4064 Kd=0.01μM versus CDCA Kd=50μM [15,31]]. Data consistent with these values were also obtained with MTT analysis following 72 hours of exposure of cell lines to each compound (data not shown).…”

Section: 1! Activation Of Fxr Induces Cell Death In Breast Cancer supporting

confidence: 86%

“…This confirms the data of Swales et al, and extends it to cover another triple negative cell line. In addition, we note Swales et al used high concentrations of GW4064 (30µM; 3,000 x Kd); here we use a lower concentration that will cause 99.9% receptor occupancy while reducing the risk of off-target effects [31]. FXR agonist-mediated activation of caspases 3/7, and subsequent PARP cleavage, is more potent in the MDA-MB-231 cell line compared to the MCF-7 cell line.…”

Section: 2! Fxr-mediated Cytotoxicity Is Mediated Through the Intrmentioning

confidence: 99%

“…However, FXR activation has also been reported to elicit a number of other phenotypes, including cell death. To confirm this phenotype in breast cancer cell lines, we examined the effect of the endogenous ligand CDCA and the more potent and selective artificial ligand GW4064 [31]. Four cell lines were chosen to represent different breast cancer phenotypes: normal (i.e.…”

Section: 1! Activation Of Fxr Induces Cell Death In Breast Cancer mentioning

confidence: 99%

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Activation of the Farnesoid X-receptor in breast cancer cell lines results in cytotoxicity but not increased migration potential

et al. 2016

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Section: 1! Activation Of Fxr Induces Cell Death In Breast Cancer supporting

confidence: 86%

Section: 2! Fxr-mediated Cytotoxicity Is Mediated Through the Intrmentioning

confidence: 99%

Section: 1! Activation Of Fxr Induces Cell Death In Breast Cancer mentioning

confidence: 99%

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Activation of the Farnesoid X-receptor in breast cancer cell lines results in cytotoxicity but not increased migration potential

et al. 2016

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“…Restoration of basal FXR expression through inhibition of DNA methylation or KRAS signaling, or through activation of residual FXR, might slow or prevent the progression of colon cancer either through direct antiproliferative or chemopreventative mechanisms. There are known FXR agonists, such as GW4064 and 6␣-ethylchenodeoxycholic acid (6E-CDCA), that are currently in preclinical and clinical development for metabolic disorders (20,29). It is conceivable that in situations where FXR is not completely absent these agents might be able to restore lost FXR activity in colon cancer resulting in inhibited tumor growth.…”

Section: G55 Mechanisms Of Fxr Silencing In Colon Cancermentioning

confidence: 99%

FXR silencing in human colon cancer by DNA methylation and KRAS signaling

Bailey

Zhan

Maru

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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Farnesoid X receptor (FXR) is a bile acid nuclear receptor described through mouse knockout studies as a tumor suppressor for the development of colon adenocarcinomas. This study investigates the regulation of FXR in the development of human colon cancer. We used immunohistochemistry of FXR in normal tissue ( n = 238), polyps ( n = 32), and adenocarcinomas, staged I–IV ( n = 43, 39, 68, and 9), of the colon; RT-quantitative PCR, reverse-phase protein array, and Western blot analysis in 15 colon cancer cell lines; NR1H4 promoter methylation and mRNA expression in colon cancer samples from The Cancer Genome Atlas; DNA methyltransferase inhibition; methyl-DNA immunoprecipitation (MeDIP); bisulfite sequencing; and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) knockdown assessment to investigate FXR regulation in colon cancer development. Immunohistochemistry and quantitative RT-PCR revealed that expression and function of FXR was reduced in precancerous lesions and silenced in a majority of stage I-IV tumors. FXR expression negatively correlated with phosphatidylinositol-4, 5-bisphosphate 3 kinase signaling and the epithelial-to-mesenchymal transition. The NR1H4 promoter is methylated in ∼12% colon cancer The Cancer Genome Atlas samples, and methylation patterns segregate with tumor subtypes. Inhibition of DNA methylation and KRAS silencing both increased FXR expression. FXR expression is decreased early in human colon cancer progression, and both DNA methylation and KRAS signaling may be contributing factors to FXR silencing. FXR potentially suppresses epithelial-to-mesenchymal transition and other oncogenic signaling cascades, and restoration of FXR activity, by blocking silencing mechanisms or increasing residual FXR activity, represents promising therapeutic options for the treatment of colon cancer.

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“…Ligand-activated FXR binds to response elements of target genes either as a classical FXRRXRa (retinoid X receptor alpha) heterodimer or as a monomer (2)(3)(4). FXR plays an important role in regulating the metabolisms of bile acid, cholesterol, triglyceride, and glucose (5).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of Human Farnesoid X Receptor by miR-421 Promotes Proliferation and Migration of Hepatocellular Carcinoma Cells

Zhang

Gong

Dai

et al. 2012

Molecular Cancer Research

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The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that is highly expressed in liver, kidney, adrenal gland, and intestine. It plays an important role in regulating the progression of several cancers including hepatocellular carcinoma (HCC). So it is necessary to study the regulation of FXR. In this study, we found that the expression of miR-421 was inversely correlated with FXR protein level in HCC cell lines. Treatment with miR-421 mimic repressed FXR translation. The reporter assay revealed that miR-421 targeted 3 0 untranslated region of human FXR mRNA. Furthermore, downregulation of FXR by miR-421 promoted the proliferation, migration, and invasion of HCC cells. These results suggest that miR-421 may serve as a novel molecular target for manipulating FXR expression in hepatocyte and for the treatment of HCC. Mol Cancer Res; 10(4); 516-22. Ó2012 AACR. IntroductionThe farnesoid X receptor (FXR) is a ligand-activated transcription factor and a member of the nuclear receptor superfamily that is mainly expressed in liver, intestine, kidney, and adrenal gland (1). Ligand-activated FXR binds to response elements of target genes either as a classical FXRRXRa (retinoid X receptor alpha) heterodimer or as a monomer (2-4). FXR plays an important role in regulating the metabolisms of bile acid, cholesterol, triglyceride, and glucose (5). Recent studies show that FXR is also involved in the regulation of liver regeneration and protection against the liver carcinogenesis (6). Therefore, FXR has received increasing attention as a therapeutic target for the treatments of certain metabolic diseases and liver carcinoma.As a multiple functional transcriptional factor, FXR regulates so many target genes, but its own regulation is not well known. It has been reported that several transcriptional coregulators, including PGC-1a, Brg-1, p300, CARM1, PRMT1, and ASCOM, can potentially modulate FXR expression (7). Moreover, glucose and insulin (8) as well as the cytokines tumor necrosis factor-a and interleukin-1 (9) have also been identified to regulate FXR level. Recently, posttranslational modifications, such as phosphorylation,

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Identification of a Chemical Tool for the Orphan Nuclear Receptor FXR

Cited by 497 publications

References 20 publications

Activation of the Farnesoid X-receptor in breast cancer cell lines results in cytotoxicity but not increased migration potential

Activation of the Farnesoid X-receptor in breast cancer cell lines results in cytotoxicity but not increased migration potential

FXR silencing in human colon cancer by DNA methylation and KRAS signaling

Downregulation of Human Farnesoid X Receptor by miR-421 Promotes Proliferation and Migration of Hepatocellular Carcinoma Cells

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