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Modulation of NKG2D ligand expression and metastasis in tumors by spironolactone via RXR-gamma activation

ABSTRACT: Tumor metastasis and lack of NKG2D ligand (NKG2DL) expression are associated with poor prognosis in patients with colon cancer. Here we found that spironolactone (SPIR), an FDA-approved diuretic drug with a long-term safety profile, can upregulate NKG2DL expression in multiple colon cancer cell lines by activating the ATM-Chk2-mediated checkpoint pathway, which in turn enhances tumor elimination by natural killer cells. SPIR can also upregulate the expression of metastasis-suppressor genes TIMP2 and TIMP3, thereby reducing tumor cell invasiveness. Although SPIR is an aldosterone antagonist, its anti-tumor effects are independent of the mineralocorticoid receptor pathway. Instead, by screening the human nuclear hormone receptor siRNA library, we identify retinoid X receptor gamma (RXR gamma) as being indispensable for the anti-tumor functions of SPIR. Collectively, our results strongly support the use of SPIR or other RXR gamma-agonists with minimal side effects for colon cancer prevention and therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE50010 | GEO | 2013/10/22

SECONDARY ACCESSION(S): PRJNA215809

REPOSITORIES: GEO

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Modulation of NKG2D ligand expression and metastasis in tumors by spironolactone via RXR-gamma activation

Project description:Tumor metastasis and lack of NKG2D ligand (NKG2DL) expression are associated with poor prognosis in patients with colon cancer. Here we found that spironolactone (SPIR), an FDA-approved diuretic drug with a long-term safety profile, can upregulate NKG2DL expression in multiple colon cancer cell lines by activating the ATM-Chk2-mediated checkpoint pathway, which in turn enhances tumor elimination by natural killer cells. SPIR can also upregulate the expression of metastasis-suppressor genes TIMP2 and TIMP3, thereby reducing tumor cell invasiveness. Although SPIR is an aldosterone antagonist, its anti-tumor effects are independent of the mineralocorticoid receptor pathway. Instead, by screening the human nuclear hormone receptor siRNA library, we identify retinoid X receptor gamma (RXR gamma) as being indispensable for the anti-tumor functions of SPIR. Collectively, our results strongly support the use of SPIR or other RXR gamma-agonists with minimal side effects for colon cancer prevention and therapy. Two replicates of two cell types with and without drug

2013-10-22 | E-GEOD-50010 | biostudies-arrayexpress

Expression data from human primary skeletal muscle myotubes treated with aldosterone, spironolactone, or vehicle.

Project description:To test for a function effect of mineralocorticoid receptor modulation in skeletal muscle, global gene expression analysis was conducted on human myltubes treated with a mineralocorticoid receptor agonist or antagonist. 9 total samples were analyzed. 3 biological replicates for each of the following treatment groups were included: 1) aldosterone; 2) spironolactone; 3) vehicle (ethanol). Pairwise comparison between groups were carried out and a fold-change ≥2 were selected.

2015-07-14 | E-GEOD-70822 | biostudies-arrayexpress

Spironolactone effect on renal RNA expression in 36 wk old NZB/W F1 female mice

Project description:The purpose of this study was to examine the effect of aldosterone receptor blockade on the immunopathogenesis and progression of nephritis in the (NZBxNZW) F1 murine lupus model. Female NZB/W F1 mice (11 weeks old) were treated daily with 25 or 50 mg/kg of oral spironolactone or vehicle. Proteinuria, renal function and serum autoantibody levels were monitored. Renal histopathology, immune complex deposition, and immunohistochemistry were analyzed at various time points. Targeted microarray analysis was performed on renal tissue, with subsequent real time PCR analysis of several differentially expressed genes. At 36 weeks of age, 8 mice from each treatment group (vehicle, 25 mg/kg/d spironolactone and 50 mg/kg/d spironolactone) were anesthetized and perfused with cold saline; then one kidney per mouse was removed , homogenized in Tripure, and frozen at -80 until RNA extraction. RNA was extracted using Tripure and a Qiagen RNEasy Minikit. RNA was pooled equally by weight within each treatment group and frozen at -80. Subsequently, the three batches of pooled RNA were processed for microarray analysis.

2010-05-26 | E-GEOD-10144 | biostudies-arrayexpress

Expression data from transgenic mice overexpressing RXR-gamma in the skeletal muscle (RXR-gamma mice)

Project description:Retinoid X receptor (RXR)-gamma is a nuclear receptor-type transcription factor expressed mostly in the skeletal muscle, and regulated by nutritional conditions. Previously, we established transgenic mice overexpressing RXR-gamma in the skeletal muscle (RXR-gamma mice), which showed lower blood glucose than the control mice. We used microarrays to investigate their glucose metabolism gene expression change. RNA was isolated from the skeletal muscle of sex- and age-matched RXR-gamma mice and non-transgenic control mice (females at 4 months of age, five samples from each group were combined). Each of the combined samples of the two groups was hybridized to the Affymetrix MG430 microarray.

2011-04-08 | E-GEOD-28447 | biostudies-arrayexpress

Expression data from transgenic mice overexpressing RXR-gamma in the skeletal muscle (RXR-gamma mice)

2011-04-08 | GSE28447 | GEO

RNAseq of the retinas of diabetic Goto-Kakizaki (GK) rats treated with spironolactone

Project description:To identify the transcriptional regulatory mechanisms associated with the biological anti-edematous and anti-inflammatory effect of spironolactone, we performed an analysis of the regulated genes in the neuroretina of GK rats aged 14 months and treated with a formulation of Spironolacton-loaded Microspheres (Sp-MSs) that released spironolactone for at least 2 months (mean size 30µm, 1µg/mg MSs/day). RNA-sequencing was performed on the neural retina and non-loade microspheres (NL-MSs) served as control treatment. The heatmaps of genes differentially regulated by Sp-MSs individuals as compared to NL-MSs showed a clear difference between the two conditions with 114 genes significantly regulated between the two groups, 27 significantly down regulated and 87 significantly up regulated (Log2FC ≥ 0,5, adjusted p<0.05). Pathway enrichment analysis using hallmark gene-set function highlighted 9 significantly regulated pathways: unfolded protein response, UV response, G2M checkpoint, allograft rejection, interferon gamma response, MTORC1 signaling, oxidative phosphorylation, MYC targets and adipogenesis (Figure EV 3B, C). Genes encoding proteins known to intervene in vascular permeability and retinal edema were counter regulated by Sp-MSs including Vldlr, Sesn2, Adcyap1, Dusp8, Pten, Slc7a1, Tjp1, Dlg1, Sema7a, although Vegf was rather up-regulated, suggested an anti-edematous mechanism independent from VEGF. The effect of Sp-MSs was confirmed by quantitative PCR for number of these genes demonstrating that spironolactone acts as a transcriptional regulator to normalize the diabetic retina.

2021-08-26 | GSE163255 | GEO

Expression data from quadriceps of utrn+/-;mdx mice treated with spironolactone plus lisinopril compared to untreated

Project description:To identify the gene expression differences in skeletal muscles resulting from treatment of dystrophic mice with spironolactone plus lisinopril

2015-07-17 | GSE70984 | GEO

Retinoid X receptor gamma signaling accelerates CNS remyelination

Project description:The molecular basis of CNS myelin regeneration (remyelination) is poorly understood. Here we generate a comprehensive transcriptional profile of the separate stages of spontaneous remyelination following focal demyelination in the rat CNS. White matter tracts in the rat caudal cerebellar peduncles were focally demyelinated using 0.1% ethidium bromide, the lesions were isolated using laser capture microdissection at 5, 14 and 28 days postlesion, followed by RNA extraction and Illumina beadarray analysis of differentially expressed transcripts. We found transcripts encoding retinoid acid receptor RXR-gamma is highly differentially expressed during remyelination, and that oligodendrocyte lineage cells express RXR-gamma in rat tissues undergoing remyelination and in active and remyelinated MS lesions. RXR-gamma knockdown by RNA interference or RXR-specific antagonists severely inhibit oligodendrocyte differentiation in culture. In RXR-gamma deficient mice, adult oligodendrocyte precursor cells efficiently repopulate lesions following demyelination, but display delayed differentiation into mature oligodendrocytes. Administration of the RXR agonist 9-cis-retinoic acid to demyelinated cerebellar slice cultures and to aged rats following demyelination results in more remyelinated axons. RXR-gamma is therefore a positive regulator of endogenous oligodendrocyte precursor cell differentiation and remyelination, and may be a pharmacological target for CNS regenerative therapy. 9 Samples analysed, 3 different time points each with 3 biological replicates.

2010-10-22 | E-GEOD-24821 | biostudies-arrayexpress

Spironolactone effect on renal RNA expression in 36 wk old NZB/W F1 female mice

2008-01-12 | GSE10144 | GEO

Homo sapiens

Project description:Modulation of NKG2D ligand expression and metastasis in tumors by spironolactone via RXR-gamma activation

| PRJNA215809 | ENA