Gamma-secretase inhibition does not affect gene expression in squamous cell carcinoma cells that do not express Notch1
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE156624 | GEO | 2020/08/22
REPOSITORIES: GEO
Similar Datasets
Project description:Gamma-secretase inhibition does not affect gene expression in squamous cell carcinoma cells that do not express Notch1
| PRJNA658531 | ENA
Project description:We identified recurrent NOTCH1 mutations in 12% of MCLs. 2 out of 10 tested MCL cell lines (Rec-1 and SP-49) were sensitive to inhibition of the NOTCH pathway by gamma-secretase inhibition. The aim of this study was to identify transcriptional targets of NOTCH signaling in MCL.
2011-12-22 | GSE34602 | GEO
Project description:Glucocorticoids are an essential component of the treatment of lymphoid malignancies and resistance to glucocorticoid therapy constitutes a prominent clinical problem in relapsed and refractory lymphoblastic leukemias. Constitutively active NOTCH signaling is involved in the pathogenesis of over 50% of T-cell lymphoblastic leukemia (T-ALL) which harbor activating mutations in the NOTCH1 gene. Aberrant NOTCH1 signaling has been shown to protect normal thymocytes from glucocorticoid induced cell death. Here we analyzed the interaction of glucocorticoid therapy with inhibition of NOTCH signaling in the treatment of T-ALL. Gamma-secretase inhibitors (GSI), which block the activation of NOTCH receptors, amplified the transcriptional changes induced by glucocorticoid treatment, including glucocorticoid receptor autoinduction and restored sensitivity to dexamethasone in glucocorticoid-resistant T-ALL cells. Apoptosis induction upon inhibition of NOTCH signaling and activation of the glucocorticoid receptor was dependent on transcriptional upregulation of BIM and subsequent activation of the mitochondrial/intrinsic cell death pathway. Finally, we used a mouse xenograft model of T-ALL to demonstrate that combined treatment with dexamethasone and a GSI results in improved antileukemic effects in vivo. These studies provide insight in the mechanisms of glucocorticoid resistance and serve as rationale for the use of glucocorticoid and GSIs in combination in the treatment of T-ALL. Experiment Overall Design: Duplicate samples (biologic replicas) from CUTLL1 cells were treated for 24 hours with vehicle only (DMSO), dexamethasone (1microM), a gamma-secretase inhibitor (CompE 100nM) and a combination of dexamethasome plus gamma secretase inhibitor at the same concentrations indicated before. Gene expression profiling was analyzed to identify gene expression signatures assocuated with glucocorticoid treatment (dexamethasone), inhibition of NOTCH1 by gamma secretase inhibitor (CompE) or the combination of both treatments.
2009-01-13 | E-GEOD-7067 | biostudies-arrayexpress
Project description:We identified recurrent NOTCH1 mutations in 12% of MCLs. 2 out of 10 tested MCL cell lines (Rec-1 and SP-49) were sensitive to inhibition of the NOTCH pathway by gamma-secretase inhibition. The aim of this study was to identify transcriptional targets of NOTCH signaling in MCL. 3 MCL cell lines (Mino, Rec-1, SP-49 treated with Mock or 1 micromolar compound E for 24 hours, in duplicate.
2011-12-22 | E-GEOD-34602 | biostudies-arrayexpress
Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer frequently associated with activating mutations in NOTCH1. Early studies identified NOTCH1 as an attractive therapeutic target for the treatment of T-ALL through the use of gamma-secretase inhibitors (GSIs). Here, we characterized the interaction between PF-03084014, a clinically-relevant GSI, and dexamethasone in preclinical models of glucocorticoid-resistant T-ALL. Combination treatment of the GSI PF-03084014 with glucocorticoids induced a synergistic antileukemic effect in human T-ALL cell lines and primary human T-ALL patient samples. Molecular characterization of the response to PF-03084014 plus glucocorticoids through gene expression profiling revealed transcriptional upregulation of the glucocorticoid receptor as the mechanism mediating the enhanced glucocorticoid response. Moreover, treatment with PF-03084014 and glucocorticoids in combination was highly efficacious in vivo, with enhanced reduction of tumor burden in a xenograft model of T-ALL. Finally, glucocorticoid treatment was highly effective at reversing PF-03084014-induced gastrointestinal toxicity via inhibition of goblet cell metaplasia. These results suggest that combination of PF-03084014 treatment with glucocorticoids may be well-tolerated and highly active for the treatment of glucorticoid-resistant T-ALL. Duplicate samples of the CUTLL1 T-ALL cell line were treated with vehicle only (DMSO), the gamma-secretase inhibitor PF-03084014 (1 microM), dexamethasone (1 microM), or PF-03084014 (1 microM). plus dexamethasone (1 microM) for 48 hours. Gene expression profiling was analyzed to identify gene expression signatures assocuated with glucocorticoid treatment (dexamethasone), inhibition of NOTCH1 by gamma secretase inhibitor (PF-03084014) or the combination of both treatments.
2011-11-09 | E-GEOD-33562 | biostudies-arrayexpress
Project description:This randomized phase I/II clinical trial is studying the side effects and best dose of gamma-secretase/notch signalling pathway inhibitor RO4929097 when given together with vismodegib and to see how well they work in treating patients with advanced or metastatic sarcoma. Vismodegib may slow the growth of tumor cells. Gamma-secretase/notch signalling pathway inhibitor RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving vismodegib together with gamma-secretase/notch signalling pathway inhibitor RO4929097 may be an effective treatment for sarcoma.
| 2091475 | ecrin-mdr-crc
Project description:γ-Secretase is involved in the regulated intramembrane proteolysis (RIP) of a variety of integral membrane proteins and generates the amyloid peptide (Aβ) in Alzheimer’s Disease (AD). Microglia are centrally involved in AD, but the substrates and function of γ-secretase in these cells remain largely unstudied. Using a novel γ-Secretase Substrate Identification (G-SECSI) method, we identified 85 substrates, of which 59 were previously unknown, in stem cell derived microglia-like cells. More than 60% of those are signalling receptors possibly involved in cell state regulation. Inhibition of γ-secretase using Semagacestat or selective genetic knockout alters the expression of homeostatic (HM) and disease-associated (DAM) genes, in particular when microglia are exposed to amyloid plaques in vivo. Thus, γ-secretase regulates tonic signaling via a spectrum of substrates in microglia in steady state, and its blockage results in the defective transition to the DAM response in AD.
2023-11-14 | PXD039238 | Pride
Project description:The intramembrane protease gamma-secretase has broad physiological functions, but also contributes to Notch-dependent tumors and Alzheimer’s disease. To identify naturally short substrates and non-substrates of gamma-secretase, we used four human cell lines of different tissue origins, breast cancer MCF7 cells, cervix carcinoma HeLa cells, T cell leukemia Jurkat cells and lymphoma U937 macrophage-like cells. The cell lines were treated overnight with the established gamma-secretase inhibitor DAPT or DMSO as a control. The proteomes of membrane fractions were determined by nano-liquid chromatography-tandem mass spectrometry and label-free quantitative proteomics. TNFRSF12A, PTPRCAP and C16orf54 were identified as potential naturally short gamma-secretase substrates, whereas other proteins with a short ectodomain including ‘pituitary tumor-transforming gene 1-interacting protein’ (PTTG1IP) did not show an increased abundance upon DAPT treatment.
2024-05-24 | PXD045701 | Pride
Project description:Presenilin mutations that alter γ-secretase activity cause familial Alzheimer's disease (AD), whereas ApoE4, an apolipoprotein for cholesterol transport, predisposes to sporadic AD. Both sporadic and familial AD feature synaptic dysfunction. Whether γ-secretase is involved in cholesterol metabolism and whether such involvement impacts synaptic function remains unknown. Here, we show that in human neurons, chronic pharmacological or genetic suppression of γ-secretase increases synapse numbers but decreases synaptic transmission by lowering the presynaptic release probability without altering dendritic or axonal arborizations. In search of a mechanism underlying these synaptic impairments, we discovered that chronic γ-secretase suppression robustly decreases cholesterol levels in neurons but not in glia, which in turn stimulates neuron-specific cholesterol-synthesis gene expression. Suppression of cholesterol levels by HMG-CoA reductase inhibitors (statins) impaired synaptic function similar to γ-secretase inhibition. Thus, γ-secretase enables synaptic function by maintaining cholesterol levels, whereas the chronic suppression of γ-secretase impairs synapses by lowering cholesterol levels.
2023-08-06 | GSE206102 | GEO
Project description:The NOTCH1 signaling pathway directly links extracellular signals with transcriptional responses in the cell nucleus and plays a critical role during T-cell development and in the pathogenesis over 50% of human T-cell lymphoblastic leukemia (T-ALL) cases. However, little is known about the transcriptional programs activated by NOTCH1. Using an integrative systems biology approach we show that NOTCH1 controls a feed-forward loop transcriptional network that promotes cell growth. Inhibition of NOTCH1 signaling in T-ALL cells led to a reduction in cell size and elicited a gene expression signature dominated by downregulated biosynthetic pathway genes. By integrating gene expression array and ChIP-on-chip data, we show that NOTCH1 directly activates multiple biosynthetic routes and induces c-MYC gene expression. Reverse engineering of regulatory networks from expression profiles showed that NOTCH1 and c-MYC govern two directly interconnected transcriptional programs containing common target genes that together regulate the growth of primary T-ALL cells. These results identify c-MYC as an essential mediator of NOTCH1 signaling and integrate NOTCH1 activation with oncogenic signaling pathways upstream of c-MYC. Experiment Overall Design: Duplicated cultures of T-ALL cell lines were treated with Compound E, a gamma-secretase inhibitor or vehicle only (DMSO) for 24 h and analyzed using oligonucleotide microarrays. Gene expression changes were analyzed in the context of loss of NOTCH1 signaling induced by the gamma secretase inhibitor treatment.
2008-06-14 | E-GEOD-5827 | biostudies-arrayexpress