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Notch regulated miRNAs in human T-ALL cell line

ABSTRACT: In an attempt to identify miRNAs regulated by oncogenic Notch signaling, we performed miRNA profiling of human T-cell acute lymphoblastic leukemia (T-ALL) cells with or without the treatment of γ-secretase inhibitor (GSI) to block Notch signaling. We found miR-223 levels to increase after GSI treatment suggesting that active Notch signaling represses miR-223 expression. We confirmed insulin-like growth factor-1 receptor (IGF1R) to be regulated by miR-223, but were unable to demonstrate functional effects on T-ALL cell growth by overexpression or knock-down of miR-223 alone.

ORGANISM(S): Human gammaherpesvirus 8 Mus musculus Rattus norvegicus JC polyomavirus Betapolyomavirus macacae Murid gammaherpesvirus 4 Homo sapiens Human immunodeficiency virus 1 Human betaherpesvirus 5 Betapolyomavirus hominis Human alphaherpesvirus 1 human gammaherpesvirus 4 Murid betaherpesvirus 1

PROVIDER: GSE35993 | GEO | 2012/05/23

SECONDARY ACCESSION(S): PRJNA151683

REPOSITORIES: GEO

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Notch regulated miRNAs in human T-ALL cell line

Project description:In an attempt to identify miRNAs regulated by oncogenic Notch signaling, we performed miRNA profiling of human T-cell acute lymphoblastic leukemia (T-ALL) cells with or without the treatment of γ-secretase inhibitor (GSI) to block Notch signaling. We found miR-223 levels to increase after GSI treatment suggesting that active Notch signaling represses miR-223 expression. We confirmed insulin-like growth factor-1 receptor (IGF1R) to be regulated by miR-223, but were unable to demonstrate functional effects on T-ALL cell growth by overexpression or knock-down of miR-223 alone. 4 samples analyzed, 2 cell lines each treated (GSI) and mock treated

2012-05-22 | E-GEOD-35993 | biostudies-arrayexpress

Human T-ALL cell line response to inhibition of Notch signaling

2011-08-01 | GSE29959 | GEO

Multilayered proteomics uncovers Notch/PKC targeting to overcome resistance to Notch inhibition in acute lymphoblastic leukemia

Project description:NOTCH1 is a crucial oncogenic driver in T-cell acute lymphoblastic leukemia (T-ALL), making it an attractive therapeutic target. However, the success of targeted therapy using γ-secretase inhibitors (GSIs), small molecules blocking Notch cleavage and subsequent activation, has been limited due to toxicity and development of resistance, thus restricting their clinical efficacy. Here we systematically compare GSI resistant and sensitive cell states by quantitative mass spectrometry-based phosphoproteomics, using complementary models of resistance, including T-ALL patient-derived xenografts (PDX) models. Our datasets reveal common mechanisms of GSI resistance, including a distinct kinase signature that involves protein kinase C delta (PKCδ). We demonstrate that the PKC inhibitor sotrastaurin enhances the anti-leukemic activity of GSI in PDX models and completely abrogates the development of acquired GSI resistance “in-vitro”. Overall, we highlight the potential of proteomics to dissect alterations in cellular signaling and identify druggable pathways in cancer.

2021-03-08 | PXD018744 | Pride

Human T-ALL cell line response to inhibition of Notch signaling

Project description:Analysis of five Notch signaling-dependent human T-ALL cell lines (ALLSIL, DND41, HPBALL, KOPTK1, TALL-1) treated with gamma-secretase inhibitor (GSI) to block Notch signaling. Samples include parental cells, cells rescued by retroviral transduction with ICN (a GSI-independent form of activated Notch1), and cells retrovirally transduced with c-Myc (an important downstream target of Notch1). Results allow segregation of bona fide Notch targets from other genes affected by gamma-secretase inhibition as well as from targets downstream of c-Myc. Thirty samples were analyzed. Five human T-ALL cell lines (ALLSIL, DND41, HPBALL, KOPTK1, TALL-1) were treated with gamma-secretase inhibitor (1.0 micromolar compound E) vs. DMSO vehicle control for 12 hours. Each cell line was also retrovirally transduced with ICN or c-Myc, FACS sorted, and then treated with GSI vs. DMSO.

2011-07-31 | E-GEOD-29959 | biostudies-arrayexpress

Vismodegib and Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Advanced or Metastatic Sarcoma

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.

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Effect of Notch Signaling Inhibitor on Gene Expression in Lipopolysaccharide-stimulated Macrophages in the Presence of Immune Complex

Project description:Lipopolysaccharide (LPS)/immunue complex (IC) stimulated macrophages produce cytokine profiles that differe from LPS-stimulated inflammatory macropahges. Notch signaling is activated in LPS/IC-stimulated macrophages and inhibition of Notch signaling reduced IL-10 production. This study investigated the effect of gamma-secretase inhibitor (GSI) that suppresses Notch signaling pathway, on gene expression profiles in macrophages activated by LPS/IC.

2018-06-21 | GSE114020 | GEO

Effect of NOTCH-γ-secretase inhibitor LY3039478 therapy on patient derived xenograft (PDX) mouse model of intrahepatic cholangiocarcinoma

Project description:Intrahepatic Cholangiocarcinoma (iCCA) is a deadly disease with rising incidence and few treatment options. Recently, aberrant Notch signaling was reported in iCCA carcinogenesis. Specifically, altered expression and/or activation of the receptors Notch1/2 suggests a role for Notch pathway overactivation during iCCA formation and progression. In this study, we examined the effects of Notch inhibition by γ-secretase inhibitor, LY3039478 in human iCCA cell lines and in an excellent patient derived-xenograft (PDX) model. Expression of several Notch pathway components, including NICD, Hes1, and DLL4, were reduced after GSI treatment. Moreover, LY3039478 inhibits cell migration and invasion while in GSI-treated mice, tumor growth was delayed compared to vehicle and chemotherapy. These results support the notion that Notch inhibition by GSI may reduce in vivo tumorigenesis. In addition, GSI reduces in PDX model VEGFA and MMP13 involved in capillary tube formation and tumor progression. Here, we therefore show a link between the efficacy of Notch inhibition and the tumor microenvironment through LY3039478 that slows tumor progression compared to control mice blocking angiogenesis via MMP13 downregulation. We used microarray technology to understand the molecular mechanisms affected by LY3039478. Cholangiocarcinoma PDX model was employed in this analysis.

2020-07-27 | GSE134114 | GEO

Differential Notch target genes expression profile upon HDAC3 loss-of-function.

Project description:The Notch signaling pathway regulates several differentiation and developmental processes in both pre- and post-natal life and its aberrant regulation leads to diseases, including cancer. Here, we investigated the role of histone deacetylase 3 (HDAC3) on the regulation of the Notch-dependent gene expression program in mouse pre-T (Beko) cells. We first defined Notch target genes as those genes that are downregulated upon inhibition of the Notch pathway using DAPT, a gamma-secretase inhibitor (GSI). Subsequently, we investigated the role of HDAC3 in the regulation of Notch target genes by shRNA- and pharmacologically (apicidin)-mediated loss-of-function of HDAC3.

2020-02-04 | GSE106361 | GEO

Pharmacological disruption of the Notch transcription factor complex

Project description:Notch pathway signaling is implicated in several human cancers. Aberrant activation and mutations of Notch signaling components are linked to tumor initiation, maintenance and resistance to cancer therapy. Several strategies, such as monoclonal antibodies (MAbs) against Notch ligands and receptors, as well as small molecule -secretase inhibitors (GSIs), have been developed to interfere with Notch receptor activation at proximal points in the pathway. However, the use of drug-like small molecules to target the downstream mediators of Notch signaling, the Notch transcription activation complex, remains largely unexplored. Using a Notch signaling dependent co-culture system, we developed a high-throughput small molecule screening assay. Herein we report the discovery of an orally active small molecule inhibitor (termed CB-103) of the Notch transcription activation complex. We show that CB-103 inhibits Notch signaling in primary human T-ALL and other Notch-dependent human tumor cell lines, and concomitantly induces cell cycle arrest, thereby impairing proliferation. Notably, CB-103 has the ability to downregulate Notch signaling in GSI-resistant human tumor cell lines that harbor chromosomal translocations and rearrangements in Notch genes. CB-103 mimics Notch loss-of-function phenotypes in flies and mice, retarding tumor growth in xenograft models of breast cancer and patient-derived xenograft models of human leukemia, notably without causing the frequently observed dose-limiting intestinal toxicity induced by other Notch inhibitors. In summary, we describe a pharmacological strategy to interfere with Notch signaling by disrupting the transcriptional regulatory complex it assembles, with therapeutic potential for the treatment of human tumors.

2020-12-19 | GSE148228 | GEO

Gene expression arrays on lung cancer cells exposed to Notch inhibitor

Project description:Genes responses in A549 and H460 cells after GSI (RO4929097-001-003 , 2 uM) treatment. Notch signaling is an area of great interest in oncology. RO4929097 is a potent and selective inhibitor of gamma-secretase, producing inhibitory activity of Notch signaling in tumor cells. The RO4929097 IC50 in cell-free and cellular assays is in the low nanomolar range with >100-fold selectivity with respect to 75 other proteins of various types (receptors, ion channels, and enzymes). RO4929097 inhibits Notch processing in tumor cells as measured by the reduction of intracellular Notch expression by Western blot. This leads to reduced expression of the Notch transcriptional target gene Hes1. RO4929097 does not block tumor cell proliferation or induce apoptosis but instead produces a less transformed, flattened, slower-growing phenotype. RO4929097 is active following oral dosing. Antitumor activity was shown in 7 of 8 xenografts tested on an intermittent or daily schedule in the absence of body weight loss or Notch-related toxicities. Importantly, efficacy is maintained after dosing is terminated. Angiogenesis reverse transcription-PCR array data show reduced expression of several key angiogenic genes. In addition, comparative microarray analysis suggests tumor cell differentiation as an additional mode of action. These preclinical results support evaluation of RO4929097 in clinical studies using an intermittent dosing schedule. A multicenter phase I dose escalation study in oncology is under way. A549 and H460 cells were treated in quadruplicate with either vehicle or GSI (RP4929097-001-003, 2 uM) for 6 or 24 hours.

2012-03-01 | E-GEOD-36176 | biostudies-arrayexpress

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