Effect of depletion of FOXO3A on gene expression of U-937 cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE218289 | GEO | 2023/08/01
REPOSITORIES: GEO
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Project description:Neuroblastoma is a pediatric tumor of the peripheral sympathetic nervous system with a highly variable prognosis. Activation of the PI3K/AKT pathway in neuroblastoma is correlated with poor patient prognosis, but the precise downstream effectors mediating this effect have not been determined. Here, we identify the forkhead transcription factor FOXO3a as a key target of the PI3K/AKT pathway in neuroblastoma. FOXO3a expression was elevated in low stage neuroblastoma tumors and normal embryonal neuroblasts, but reduced in late stage neuroblastoma. Inactivation of FOXO3a by AKT was essential for neuroblastoma cell survival. Treatment of neuroblastoma cells with the dual PI3K/mTOR inhibitor PI-103 activated FOXO3a and triggered apoptosis. This effect was rescued by FOXO3a silencing. Conversely, apoptosis induced by PI-103 or the AKT inhibitor MK-2206 was potentiated by FOXO3a overexpression. Further, levels of total or phosphorylated FOXO3a correlated closely with apoptotic sensitivity to MK-2206. In clinical specimens, there was an inverse relationship between gene expression signatures regulated by PI3K signaling and FOXO3a transcriptional activity. Moreover, high PI3K activity and low FOXO3a activity were each associated with an extremely poor prognosis. Our work indicates that expression of FOXO3a and its targets offer useful prognostic markers as well as biomarkers for PI3K/AKT inhibitor efficacy in neuroblastoma.
2013-05-01 | GSE42762 | GEO
Project description:Neuroblastoma is a pediatric tumor of the peripheral sympathetic nervous system with a highly variable prognosis. Activation of the PI3K/AKT pathway in neuroblastoma is correlated with poor patient prognosis, but the precise downstream effectors mediating this effect have not been determined. Here, we identify the forkhead transcription factor FOXO3a as a key target of the PI3K/AKT pathway in neuroblastoma. FOXO3a expression was elevated in low stage neuroblastoma tumors and normal embryonal neuroblasts, but reduced in late stage neuroblastoma. Inactivation of FOXO3a by AKT was essential for neuroblastoma cell survival. Treatment of neuroblastoma cells with the dual PI3K/mTOR inhibitor PI-103 activated FOXO3a and triggered apoptosis. This effect was rescued by FOXO3a silencing. Conversely, apoptosis induced by PI-103 or the AKT inhibitor MK-2206 was potentiated by FOXO3a overexpression. Further, levels of total or phosphorylated FOXO3a correlated closely with apoptotic sensitivity to MK-2206. In clinical specimens, there was an inverse relationship between gene expression signatures regulated by PI3K signaling and FOXO3a transcriptional activity. Moreover, high PI3K activity and low FOXO3a activity were each associated with an extremely poor prognosis. Our work indicates that expression of FOXO3a and its targets offer useful prognostic markers as well as biomarkers for PI3K/AKT inhibitor efficacy in neuroblastoma. Affymetrix U133 Plus 2.0 profiling of SY5Y-TetR-FOXO3A cells treated with doxycycline and/or the PI3K/mTOR inhibitor PI-103. Each condition profiled in triplicate.
2013-05-01 | E-GEOD-42762 | biostudies-arrayexpress
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Project description:We employed microarray expression profiling to identify genes which are differentially regulated in the absence of FoxO3a, upon Salmonella typhimurium (ST) infection. ST induced gene expression changes were measured in Wild-type and FoxO3a-/- bone marrow derived macroophages at 6 hours post infection. The array showed an enrichment of MAPK signaling and alterations in inflammatory cytokines and ROS regulators in the absence of FoxO3a. Gene expression changes in bone marrow derived macrophages was measured after infection with 10 MOI of Salmonella typhimurium. Control samples were left untreated. Two mice from each genotype were used for the experiment.
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Project description:We established a model system in human DLD1 colon cancer cells to study the transcriptional crosstalk between FOXO3A and beta-Catenin. Thereby, translocation to the nucleus of a AKT-insensitive mutant (T32A, S253A, S315A) of human FOXO3A fused to the ligand binding domain of human estrogen receptor can be induced by exposure to 4-hydroxy-tamoxifen. Furthermore, expression of a stable mutant (S33Y) of human beta-catenin is doxycycline inducible. Addition of those drugs separately or in combination allows identification of common or excusive target gene sets.
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Project description:Effect of depletion of FOXO3A on gene expression of U-937 cells
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