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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. Two replicates of two cell types with and without drug

ORGANISM(S): Homo sapiens

SUBMITTER: David Finkelstein

PROVIDER: E-GEOD-50010 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.

2013-10-22 | GSE50010 | GEO

Homo sapiens

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

| PRJNA215809 | ENA

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

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

Retinoid X receptor gamma signaling accelerates CNS remyelination

2010-10-22 | GSE24821 | GEO

Genome-wide profiling of PPAR?:RXR and RNA polymerase II

Project description:Genome-wide profiling of PPAR?:RXR and RNA polymerase II reveals temporal activation of distinct metabolic pathways in RXR dimer composition during adipogenesis. Chromatin immunoprecipitation combined with deep sequencing was performed to generate genome-wide maps of peroxisome prolifelator-activated receptor gamma (PPARg) and retinoid X receptor (RXR) binding sites, and RNA polymerase II (RNAPII) occupancy at high resolution throughout adipocyte differentiation of 3T3-L1 cells. The data provides the first positional and temporal map PPAR? and RXR occupancy during adipocyte differentiation at a global scale. The number of PPAR?:RXR shared binding sites is steadily increasing from D0 to D6. At Day6 there are over 5000 high confidence shared PPARy:RXR binding sites. We show that at the early days of differentiation several of these sites bind not only PPAR?:RXR but also other RXR dimers. The data also provides a comprehensive temporal map of RNAPII occupancy at genes throughout 3T3-L1 adipogenesis thereby uncovering groups of similarly regulated genes belonging to glucose and lipid metabolic pathways. The majority of the upregulated but very few downregulated genes have assigned PPAR?:RXR target sites, thereby underscoring the importance of PPAR?:RXR in gene activation during adipogenesis and indicating that a hitherto unrecognized high number of adipocyte genes are directly activated by PPAR?:RXR Examination of PPARg and RXR bindingsites during adipocyte differentiation (day 0 to 6) and association with transcription via RNAPII occupancy.

2008-12-10 | E-GEOD-13511 | biostudies-arrayexpress

EMT alterations in the solute carrier landscape uncover SLC22A10/A15 imposed vulnerabilities in pancreatic cancer

Project description:<p>The involvement of membrane-bound solute carriers (SLCs) in neoplastic transdifferentiation processes is poorly defined. Here, we examined changes in the SLC landscape during epithelial-mesenchymal transition (EMT) of pancreatic cancer cells. We show that two SLCs from the organic anion/cation transporter family, SLC22A10 and SLC22A15, favor EMT via interferon (IFN) α and γ signaling activation of receptor tyrosine kinase-like orphan receptor 1 (ROR1) expression. In addition, SLC22A10 and SLC22A15 allow tumor cell accumulation of glutathione to support EMT via the IFNα/γ-ROR1 axis. Moreover, a pan-SLC22A inhibitor lesinurad reduces EMT-induced metastasis and gemcitabine chemoresistance to prolong survival in mouse models of pancreatic cancer, thus identifying new vulnerabilities for human PDAC.</p>

2021-10-15 | MTBLS1925 | MetaboLights

Mus musculus

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

| PRJNA139261 | ENA

Genome-wide profiling of PPARγ:RXR and RNA polymerase II

Project description:Genome-wide profiling of PPARγ:RXR and RNA polymerase II reveals temporal activation of distinct metabolic pathways in RXR dimer composition during adipogenesis. Chromatin immunoprecipitation combined with deep sequencing was performed to generate genome-wide maps of peroxisome prolifelator-activated receptor gamma (PPARg) and retinoid X receptor (RXR) binding sites, and RNA polymerase II (RNAPII) occupancy at high resolution throughout adipocyte differentiation of 3T3-L1 cells. The data provides the first positional and temporal map PPARγ and RXR occupancy during adipocyte differentiation at a global scale. The number of PPARγ:RXR shared binding sites is steadily increasing from D0 to D6. At Day6 there are over 5000 high confidence shared PPARy:RXR binding sites. We show that at the early days of differentiation several of these sites bind not only PPARγ:RXR but also other RXR dimers. The data also provides a comprehensive temporal map of RNAPII occupancy at genes throughout 3T3-L1 adipogenesis thereby uncovering groups of similarly regulated genes belonging to glucose and lipid metabolic pathways. The majority of the upregulated but very few downregulated genes have assigned PPARγ:RXR target sites, thereby underscoring the importance of PPARγ:RXR in gene activation during adipogenesis and indicating that a hitherto unrecognized high number of adipocyte genes are directly activated by PPARγ:RXR

2008-12-10 | GSE13511 | GEO

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