Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA138895 | ENA |
REPOSITORIES: ENA
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Project description:A synthetic analog of sphingosine named FTY720 (Fingolimod), phosphorylated by sphingosine kinase-2, interacts with sphingosine-1-phosphate (S1P) receptors expressed on various cells. FTY720 suppresses the disease activity of multiple sclerosis (MS) chiefly by inhibiting S1P-dependent egress of autoreactive T lymphocytes from secondary lymphoid organs, and possibly by exerting anti-inflammmatory and neuroprotective effects directly on brain cells. However, at present, biological effects of FTY720 on human microglia are largely unknown. We studied FTY720-mediated apoptosis of a human microglia cell line HMO6. The exposure of HMO6 cells to non-phosphorylated FTY720 (FTY720-non-P) induced apoptosis in a dose-dependent manner with IC50 of 10.6±2.0 microM, accompanied by the cleavage of caspase-7 and caspase-3 but not of caspase-9. The apoptosis was inhibited by Z-DQMD-FMK, a caspase-3 inhibitor, but not by Pertussis toxin, a Gi protein inhibitor, suramin, a S1P3/S1P5 inhibitor, or W123, a S1P1 competitive antagonist, although HMO6 expressed S1P1, S1P2, and S1P3. Furthermore, both phosphorylated FTY720 (FTY720-P) and SEW2871, a S1P1 selective agonist did not induce apoptosis of HMO6. Genome-wide gene expression profiling and molecular network analysis indicated activation of transcriptional regulation by sterol regulatory element-binding protein (SREBP) in FTY720-non-P-treated HMO6 cells. Western blot verified activation of SREBP2 in these cells, and apoptosis was enhanced by pretreatment with simvastatin, an activator of SREBP2, and by overexpression of the N-terminal fragment of SREBP2. These observations suggest that FTY720-non-P-induced apoptosis of HMO6 human microglia is independent of S1P receptor binding, and positively regulated by the SREBP2-dependent proapoptotic signaling pathway. The HMO6 cell line was established by immortalizing cultured microglia isolated from human embryonic telencephalon tissues with a retroviral vector PASK1.2 encoding v-myc oncogene (Nagai et al. Neurobiol. Dis. 8: 1057-1068, 2001). HMO6 cells express the markers of the microglia/macrophage lineage cells, including CD11b, CD68, CD86, HLA-ABC, HLA-DR, and ricinus communis agglutinin lectin-1 (RCA), serving as a model of human microglia both in vitro and in vivo. The cells were exposed for 2 hours to 10 microM FTY720-non-P dissolved in dimethyl sulfoxide (DMSO) or ethanol or exposed to the vehicle.
2011-04-16 | E-GEOD-28642 | biostudies-arrayexpress
Project description:A synthetic analog of sphingosine named FTY720 (Fingolimod), phosphorylated by sphingosine kinase-2, interacts with sphingosine-1-phosphate (S1P) receptors expressed on various cells. FTY720 suppresses the disease activity of multiple sclerosis (MS) chiefly by inhibiting S1P-dependent egress of autoreactive T lymphocytes from secondary lymphoid organs, and possibly by exerting anti-inflammmatory and neuroprotective effects directly on brain cells. However, at present, biological effects of FTY720 on human microglia are largely unknown. We studied FTY720-mediated apoptosis of a human microglia cell line HMO6. The exposure of HMO6 cells to non-phosphorylated FTY720 (FTY720-non-P) induced apoptosis in a dose-dependent manner with IC50 of 10.6±2.0 microM, accompanied by the cleavage of caspase-7 and caspase-3 but not of caspase-9. The apoptosis was inhibited by Z-DQMD-FMK, a caspase-3 inhibitor, but not by Pertussis toxin, a Gi protein inhibitor, suramin, a S1P3/S1P5 inhibitor, or W123, a S1P1 competitive antagonist, although HMO6 expressed S1P1, S1P2, and S1P3. Furthermore, both phosphorylated FTY720 (FTY720-P) and SEW2871, a S1P1 selective agonist did not induce apoptosis of HMO6. Genome-wide gene expression profiling and molecular network analysis indicated activation of transcriptional regulation by sterol regulatory element-binding protein (SREBP) in FTY720-non-P-treated HMO6 cells. Western blot verified activation of SREBP2 in these cells, and apoptosis was enhanced by pretreatment with simvastatin, an activator of SREBP2, and by overexpression of the N-terminal fragment of SREBP2. These observations suggest that FTY720-non-P-induced apoptosis of HMO6 human microglia is independent of S1P receptor binding, and positively regulated by the SREBP2-dependent proapoptotic signaling pathway.
2011-04-16 | GSE28642 | GEO
Project description:Although microglial have an essential role in host defense in the brain, the abnormal activation of microglia can lead to devastating outcomes, such as neuroinflammation and neurodegeneration. Emerging evidence increasingly supports that FTY720 (fingolimod), an FDA-approved drug has beneficial effects in the CNS on brain cells and more recently immunosuppressive activities in microglia via modulation of the S1P1 receptor. However, the exact molecular aspects of FTY720 contribution in microglia remain largely unaddressed. To understand the molecular mechanisms underlying the roles of FTY720 in microglia, we performed gene expression profiling in resting, FTY720, LPS and LPS+FTY720 challenged primary microglial cells (PM) isolated from 3-day-old ICR mice and we identified FTY720 target genes and co-regulated modules that were critical in inflammation. By examining RNA-sequencing and binding motif datasets from FTY720 suppressed LPS-induced inflammatory mediators, we also identified unexpected relationships between the inducible transcription factors (TFs), motif strength, and transcription of key inflammatory mediators. Furthermore, we show that FTY720 controls important inflammatory genes targets by modulating STAT1, and IRF8 level at their promoter site. Our unprecedented findings demonstrate that FTY720 could be a useful therapeutic application for neuroinflammatory diseases associated with microglia activation as well as provide a rich resource and framework for future analyses of FTY720 on microglia interaction.
2017-11-27 | GSE90932 | GEO
Project description:FTY720/Fingolimod, an FDA-approved drug for treatment of multiple sclerosis, has beneficial effects in the CNS that are not yet well understood, independent of its effects on immune cell trafficking. Here we show that FTY720 enters the nucleus where it is phosphorylated by sphingosine kinase 2 (SphK2) and nuclear FTY720-P that accumulates there, binds and inhibits class I histone deacetylases (HDACs) enhancing specific histone acetylations. FTY720 is also phosphorylated in mice and accumulates in various brain regions, including hippocampus, inhibits HDACs and enhances histone acetylation and gene expression programs associated with memory and learning leading to improvement of memory impairment independently of its immunosuppressive actions. Our data suggest that sphingosine-1-phosphate and SphK2 play specific roles in memory functions and that FTY720 may be a useful adjuvant therapy to facilitate extinction of aversive memories. Microarrays were used to survey the effect of FTY720 treatment during contextual fear conditioning on hippocampal gene expression. Total RNA was isolated from individual hippocampi of SCID mice 1 hour following fear consolidation testing after the third day of FTY720 or saline treatment. Eight arrays were run in total: 4 FTY720-treated mice and 4 saline-treated control mice.
2014-05-12 | E-GEOD-57015 | biostudies-arrayexpress
Project description:FTY720/Fingolimod, an FDA-approved drug for treatment of multiple sclerosis, has beneficial effects in the CNS that are not yet well understood, independent of its effects on immune cell trafficking. Here we show that FTY720 enters the nucleus where it is phosphorylated by sphingosine kinase 2 (SphK2) and nuclear FTY720-P that accumulates there, binds and inhibits class I histone deacetylases (HDACs) enhancing specific histone acetylations. FTY720 is also phosphorylated in mice and accumulates in various brain regions, including hippocampus, inhibits HDACs and enhances histone acetylation and gene expression programs associated with memory and learning leading to improvement of memory impairment independently of its immunosuppressive actions. Our data suggest that sphingosine-1-phosphate and SphK2 play specific roles in memory functions and that FTY720 may be a useful adjuvant therapy to facilitate extinction of aversive memories. Microarrays were used to survey the effect of FTY720 treatment during contextual fear conditioning on hippocampal gene expression.
2014-05-12 | GSE57015 | GEO
Project description:Nuclear FTY720-P is a potent inhibitor of class I histone deacetylases (HDACs) that enhances histone acetylations and regulates expression of a restricted set of genes independently of its known effects on canonical signaling through sphingosine-1-phosphate (S1P) receptors. We found that FTY720 is phosphorylated in Era-negative breast cancer cells by nuclear sphingosine kinase 2 and accumulates these cells.
2015-06-03 | GSE69462 | GEO
Project description:: FTY720 (Fingolimod) is an immunosuppressive drug approved by FDA for Multiple Sclerosis (MS), that has gained attention as anti-cancer drug, thanks to its ability to disrupt the binding between the onco-protein SET and the tumor- suppressor phosphatase PP2A. We investigated FTY720 induced phospho-proteomic changes on acute myeloid leukemia cell lines carrying KMT2A-transocations. The phospho-proteomic data indicated that FTY720 treatment resulted in the down-regulation of phospho-sites associated to protein serine/threonine kinase activity, chromatin organisation and transcription. The findings support the hypothesis of a feedback loop between SET, PP2A and MYC, whereby FTY720 re-activates PP2A with an overall inhibitory effect on MYC, resulting in cell cycle arrest and apoptosis.
2024-01-26 | PXD038288 | Pride
Project description:The clinical outcomes of M2 subtype Acute Myeloid Leukemia (AML-M2) with t(8;21) are poor. Here we report that FTY720 (Fingolimod), a sphingosine analogue and an FDA approved drug for treatment of multiple sclerosis, showed great antitumorigenic activity against Kasumi-1 cell line, xenograft mouse model and leukemic blasts isolated from AML-M2 with t(8;21) patients. Primary investigation indicated that FTY720 caused cell apoptosis through caspase and protein phosphatase 2A (PP2A) activation. Transcriptomic profiling further revealed that FTY720 treatment could upregulate AML1 target genes and interfere with genes involved in ceramide synthesis. FTY720 treatment led to the elimination of AML1-ETO oncoprotein and caused cell cycle arrest. More importantly, FTY720 treatment resulted in rapid and significant increment of pro-apoptotic ceramide levels, determined by HPLC-ESI-MS/MS (high-performance liquid chromatography-electrospray ionization tandem mass spectrometry) based lipidomic approaches. Additionally, structural simulation model indicated that the directly binding of ceramide to inhibitor 2 of PP2A (I2PP2A) could reactivate PP2A and cause cell death. This study demonstrates, for the first time, that accumulation of ceramide plays a central role in FTY720 induced cell death of AML-M2 with t(8;21). Targeting sphingolipid metabolism by using FTY720 may provide novel insight into drug development for AML-M2 treatment. A six chip study using total RNA recovered from three separate cultures of DMSO-treated Kasumi-1 cells and three separate cultures of FTY720-treated Kasumi-1 cells.Each chip measures the expression level of genes from DMSO-/FTY720-treated Kasumi-1 cells.
2014-04-30 | E-GEOD-55772 | biostudies-arrayexpress
Project description:The clinical outcomes of M2 subtype Acute Myeloid Leukemia (AML-M2) with t(8;21) are poor. Here we report that FTY720 (Fingolimod), a sphingosine analogue and an FDA approved drug for treatment of multiple sclerosis, showed great antitumorigenic activity against Kasumi-1 cell line, xenograft mouse model and leukemic blasts isolated from AML-M2 with t(8;21) patients. Primary investigation indicated that FTY720 caused cell apoptosis through caspase and protein phosphatase 2A (PP2A) activation. Transcriptomic profiling further revealed that FTY720 treatment could upregulate AML1 target genes and interfere with genes involved in ceramide synthesis. FTY720 treatment led to the elimination of AML1-ETO oncoprotein and caused cell cycle arrest. More importantly, FTY720 treatment resulted in rapid and significant increment of pro-apoptotic ceramide levels, determined by HPLC-ESI-MS/MS (high-performance liquid chromatography-electrospray ionization tandem mass spectrometry) based lipidomic approaches. Additionally, structural simulation model indicated that the directly binding of ceramide to inhibitor 2 of PP2A (I2PP2A) could reactivate PP2A and cause cell death. This study demonstrates, for the first time, that accumulation of ceramide plays a central role in FTY720 induced cell death of AML-M2 with t(8;21). Targeting sphingolipid metabolism by using FTY720 may provide novel insight into drug development for AML-M2 treatment.
2014-04-30 | GSE55772 | GEO
Project description:Oral FTY720 treatment of mice with experimental autoimmune encephalomyelitis leads to B cell-specific effects of the drug, which comprise the induction of apoptosis and the modulation of B cell receptor signaling.
2017-08-11 | GSE101753 | GEO