Comparison of gene expression alterations induced by distinct PI3K inhibitors
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Brachmann SM
PROVIDER: S-ECPF-GEOD-33643 | biostudies-other | 2012 Aug
REPOSITORIES: biostudies-other
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Project description:The goal is the characterization of the off-target activity of BKM120 observed in A2058 human melanoma cell line at IC90 concentration (3.606 µM) but not at lower concentrations. Controls are BEZ235, GDC0941, showing no off-target activity. A secondary objective is the characterizations of drug effects on transcript expression with respect to a control treatment (DMSO) of those PI3K inhibitors. 3 compounds, 3 concentrations per compound treatment, DMSO control treatement, 4 biological replicates
2012-06-30 | E-GEOD-33643 | biostudies-arrayexpress
Project description:The goal is the characterization of the off-target activity of BKM120 observed in A2058 human melanoma cell line at IC90 concentration (3.606 µM) but not at lower concentrations. Controls are BEZ235, GDC0941, showing no off-target activity. A secondary objective is the characterizations of drug effects on transcript expression with respect to a control treatment (DMSO) of those PI3K inhibitors.
2012-07-01 | GSE33643 | GEO
Project description:Activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is one the most frequent genetic events in human cancer. Therefore, the development of PI3K inhibitors has attracted much attention. We previously described the pyrazolopyrimidine derivative ETP-45658 as a potent inhibitor of PI3K p110α in vitro and in vivo. Here we report the gene expression signatures of MCF7 cells treated with ETP-45658 or the reference PI3K inhibitor PI-103. Both compounds potently inhibited proliferation of a wide range of human cancer cells. ETP-45658 most potently suppressed the growth of PIK3CA (E545K)-mutated MCF7 breast cancer cells. Treatment with ETP-45658 or PI-103 resulted in a time and concentration-dependent decrease in phosphorylation of AKT Ser473 in MCF7 cells. We conducted microarray analysis examining the gene expression profile in MCF7 cells at six hours post ETP-45658 or PI-103 incubation. Both compounds induced the expression of negative cell cycle regulators including Cyclin G2, p27kip1 and ING4 and decreased positive regulators such as Cyclin D1 without significantly affecting the expression of pro-apoptotic genes. We found FOXO transcription factor binding sites over-represented in both up- and down-regulated genes but not in those without significant changes. The expression of the breast cancer tumor suppressor Nischarin was found to be induced by ETP-45658 but not after PI-103 treatment while several genes differentially expressed specifically after ETP-45658 treatment are functionally associated with the focal adhesion pathway. Twelve samples have been analyzed in six different conditions. Two replicates have been included for each condition.
| S-ECPF-GEOD-56579 | biostudies-other
Project description:The activation of the PI3K signaling pathway resulting from genetic alterations induces carcinogenesis and resistance to anticancer therapies. Breast cancer is a major malignancy that is associated with dysregulation of the PI3K signaling pathway. PIK3CA mutations and PTEN loss occur in every subtype of breast cancer. PI3K inhibitors are being evaluated in breast cancer after the success of an alpha isoform-specific PI3K inhibitor in estrogen receptor (ER)-positive/HER2-negative metastatic breast cancer. Some preclinical data indicate the potential for PI3K/mTOR targeting in combination with trastuzumab for HER2-positive breast cancer with or without expression of the estrogen receptor. However, the role of this therapy in HER2-positive breast cancer with PIK3CA mutations and/or PTEN loss remains unclear. We examined three HER2-positive, ER-negative breast cancer cell lines to determine the efficacy of a novel alpha isoform-specific PI3K inhibitor in combination with trastuzumab. The results indicated that this combination was effective in PIK3CA-mutant or PTEN-deficient breast cancer cells by inducing apoptosis and inhibiting the expression of downstream proteins. PTEN loss by siRNA modulation in parental HER2-positive cancer cells with PI3K signaling pathway alterations could not confer resistance to alpelisib or GDC-0077 plus trastuzumab. We selected the CK-MB-1 cell line without alterations in the PI3K pathway to demonstrate that PI3K inhibitors plus trastuzumab represented a biomarker-specific treatment. In vivo effects of alpelisib plus trastuzumab were tested and confirmed in a mouse model, showing the combination strategy offered the best opportunity to achieve tumor volume reduction. With known safety profiles, this cytotoxic chemotherapy-free regimen warrants further attention as a biomarker-driven strategy for treating HER2-positive breast cancer.
| S-EPMC9360227 | biostudies-literature
Project description:Pathologic and epidemiologic evidence has led to a histologic model of breast cancer progression that involves advancement through specific morphologic stages including atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) and invasive mammary carcinoma (IMC), although not necessarily always in a linear fashion. Numerous observational studies have examined genetic, epigenetic and gene expression differences in breast tissues representing these different stages of progression, but model systems which would allow for experimental testing of specific factors influencing transition through these stages are scarce. The 21T series cell lines, all originally derived from the same patient with metastatic breast cancer, have been proposed to represent a mammary tumor progression series. We report here that three of the 21T cell lines indeed mimic specific stages of human breast cancer progression (21PT-derived cells, ADH; 21NT-derived cells, DCIS; 21MT-1 cells, IMC) when grown in the mammary fat pad of nude mice, albeit after up to a year post-injection. In order to develop a more rapid, readily manipulatable in vitro assay for examining the biologic differences between these cell lines, we have made use of a 3D Matrigel system. When grown in 3D Matrigel, we have found characteristic morphologies of the three cell lines in which quantifiable aspects of the stage-specific in vivo behaviors (i.e. differences in acinar structure formation, cell polarization, cell cohesiveness, cell proliferation, cell invasion) are re-capitulated in a reproducible fashion. Gene expression profiling has revealed a characteristic pattern for each of the three cell lines. Interestingly, WNT pathway alterations are particularly predominant in the early transition from 21PTci (ADH) to 21NTci (DCIS), whereas alterations in expression of genes associated with control of cell motility and invasiveness phenomena are more prominent in the later transition of 21NTci (DCIS) to 21MT-1 (IMC). This system thus reveals potential therapeutic targets and will provide a means of testing the influences of identified genes on transitions between these stages of pre-malignant to malignant growth. Keywords: DCIS or IDC vs ADH RNA derived from three biological replicates of a cell line representing atypical ductal hyperplasia (ADH), Ductal carcinoma in situ (DCIS), and Invasive ductal carcinoma (IDC)
| S-ECPF-GEOD-18370 | biostudies-other
Project description:Hyperactivation of the phosphatydil-inositol-3' phosphate kinase (PI3K)/AKT pathway is observed in most NSCLCs, promoting proliferation, migration, invasion and resistance to therapy. AKT can be activated through several mechanisms that include loss of the negative regulator PTEN, activating mutations of the catalytic subunit of PI3K (PIK3CA) and/or mutations of AKT1 itself. However, number and identity of downstream targets of activated PI3K/AKT pathway are poorly defined. To identify the genes that are targets of constitutive PI3K/AKT signalling in lung cancer cells, we performed a comparative transcriptomic analysis of human lung epithelial cells (BEAS-2B) expressing active mutant AKT1 (AKT1-E17K), active mutant PIK3CA (PIK3CA-E545K) or that are silenced for PTEN. We found that, altogether, aberrant PI3K/AKT signalling in lung epithelial cells regulated the expression of 1,960/20,436 genes (9%), though only 30 differentially expressed genes (DEGs) (15 up-regulated, 12 down-regulated and 3 discordant) out of 20,436 that were common among BEAS-AKT1-E17K, BEAS-PIK3CA-E545K and BEAS-shPTEN cells (0.1%). Conversely, DEGs specific for mutant AKT1 were 133 (85 up-regulated; 48 down-regulated), DEGs specific for mutant PIK3CA were 502 (280 up-regulated; 222 down-regulated) and DEGs specific for PTEN loss were 1549 (799 up-regulated, 750 down-regulated). The results obtained from array analysis were confirmed by quantitative RT-PCR on selected up- and down-regulated genes (n = 10). Treatment of BEAS-C cells and the corresponding derivatives with pharmacological inhibitors of AKT (MK2206) or PI3K (LY294002) further validated the significance of our findings. Moreover, mRNA expression of selected DEGs (SGK1, IGFBP3, PEG10, GDF15, PTGES, S100P, respectively) correlated with the activation status of the PI3K/AKT pathway assessed by S473 phosphorylation in NSCLC cell lines (n = 6). Finally, we made use of Ingenuity Pathway Analysis (IPA) to investigate the relevant BioFunctions enriched by the costitutive activation of AKT1-, PI3K- or PTEN-dependent signalling in lung epithelial cells. Expectedly, the analysis of the DEGs common to all three alterations highlighted a group of BioFunctions that included Cell Proliferation of tumor cell lines (14 DEGs), Invasion of cells (10 DEGs) and Migration of tumour cell lines (10 DEGs), with a common core of 5 genes (ATF3, CDKN1A, GDF15, HBEGF and LCN2) that likely represent downstream effectors of the pro-oncogenic activities of PI3K/AKT signalling. Conversely, IPA analysis of exclusive DEGs led to the identification of different downstream effectors that are modulated by mutant AKT1 (TGFBR2, CTSZ, EMP1), mutant PIK3CA (CCND2, CDK2, IGFBP2, TRIB1) and PTEN loss (ASNS, FHL2). These findings not only shed light on the molecular mechanisms that are activated by aberrant signalling through the PI3K/AKT pathway in lung epithelial cells, but also contribute to the identification of previously unrecognised molecules whose regulation takes part in the development of lung cancer.
| S-EPMC5491004 | biostudies-literature
Project description:BackgroundDiabetes profoundly affects gene expression in organs such as heart, skeletal muscle, kidney and liver, with areas of perturbation including carbohydrate and lipid metabolism, oxidative stress, and protein ubiquitination. Type 1 diabetes impairs lung function, but whether gene expression alterations in the lung parallel those of other tissue types is largely unexplored.MethodsLung from a rat model of diabetes mellitus induced by streptozotocin was subjected to gene expression microarray analysis.ResultsGlucose levels were 67 and 260 mg/dl (p < 0.001) in control and diabetic rats, respectively. There were 46 genes with at least ± 1.5-fold significantly altered expression (19 increases, 27 decreases). Gene ontology groups with significant over-representation among genes with altered expression included apoptosis, response to stress (p = 0.03), regulation of protein kinase activity (p = 0.04), ion transporter activity (p = 0.01) and collagen (p = 0.01). All genes assigned to the apoptosis and response to stress groups had increased expression whereas all genes assigned to the collagen group had decreased expression. In contrast, the protein kinase activity and ion transporter activity groups had genes with both increased and decreased expression.ConclusionsGene expression in the lung is affected by type 1 diabetes in several specific areas, including apoptosis. However, the lung is resistant to changes in gene expression related to lipid and carbohydrate metabolism and oxidative stress that occur in other tissue types such as heart, skeletal muscle and kidney.
| S-EPMC3945062 | biostudies-literature
Project description:Activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is one the most frequent genetic events in human cancer. Therefore, the development of PI3K inhibitors has attracted much attention. We previously described the pyrazolopyrimidine derivative ETP-45658 as a potent inhibitor of PI3K p110α in vitro and in vivo. Here we report the gene expression signatures of MCF7 cells treated with ETP-45658 or the reference PI3K inhibitor PI-103. Both compounds potently inhibited proliferation of a wide range of human cancer cells. ETP-45658 most potently suppressed the growth of PIK3CA (E545K)-mutated MCF7 breast cancer cells. Treatment with ETP-45658 or PI-103 resulted in a time and concentration-dependent decrease in phosphorylation of AKT Ser473 in MCF7 cells. We conducted microarray analysis examining the gene expression profile in MCF7 cells at six hours post ETP-45658 or PI-103 incubation. Both compounds induced the expression of negative cell cycle regulators including Cyclin G2, p27kip1 and ING4 and decreased positive regulators such as Cyclin D1 without significantly affecting the expression of pro-apoptotic genes. We found FOXO transcription factor binding sites over-represented in both up- and down-regulated genes but not in those without significant changes. The expression of the breast cancer tumor suppressor Nischarin was found to be induced by ETP-45658 but not after PI-103 treatment while several genes differentially expressed specifically after ETP-45658 treatment are functionally associated with the focal adhesion pathway. Twelve samples have been analyzed in six different conditions. Two replicates have been included for each condition.
2014-04-08 | E-GEOD-56579 | biostudies-arrayexpress
Project description:BackgroundSkin atrophy is a major adverse effect of topical glucocorticoids. We recently reported that REDD1 (regulated in development and DNA damage 1) and FKBP51 (FK506 binding protein 5), negative regulators of mTOR/Akt signaling, are induced by glucocorticoids in mouse and human skin and are central drivers of steroid skin atrophy. Thus, we hypothesized that REDD1/FKBP51 inhibitors could protect skin against catabolic effects of glucocorticoids.MethodsUsing drug repurposing approach, we screened LINCS library (http://lincsproject.org/LINCS/) to identify repressors of REDD1/FKBP51 expression. Candidate compounds were tested for their ability to inhibit glucocorticoid-induced REDD1/FKBP51 expression in human primary/immortalized keratinocytes and in mouse skin. Reporter gene expression, microarray, and chromatin immunoprecipitation were employed to evaluate effect of these inhibitors on the glucocorticoid receptor (GR) signaling.FindingsBioinformatics analysis unexpectedly identified phosphoinositide-3-kinase (PI3K)/mTOR/Akt inhibitors as a pharmacological class of REDD1/FKBP51 repressors. Selected PI3K/mTOR/Akt inhibitors-Wortmannin (WM), LY294002, AZD8055, and two others indeed blocked REDD1/FKBP51expression in human keratinocytes. PI3K/mTOR/Akt inhibitors also modified global effect of glucocorticoids on trascriptome, shifting it towards therapeutically important transrepression; negatively impacted GR phosphorylation; nuclear translocation; and GR loading on REDD1/FKBP51 gene promoters. Further, topical application of LY294002 together with glucocorticoid fluocinolone acetonide (FA) protected mice against FA-induced proliferative block and skin atrophy but did not alter the anti-inflammatory activity of FA in ear edema test.InterpretationOur results built a strong foundation for development of safer GR-targeted therapies for inflammatory skin diseases using combination of glucocorticoids with PI3K/mTOR/Akt inhibitors. FUND: Work is supported by NIH grants R01GM112945, R01AI125366, and HESI-THRIVE foundation.
| S-EPMC6441871 | biostudies-literature
Project description:Mammalian reovirus infection results in perturbation of host cell cycle progression. Since reovirus infection is known to activate cellular transcription factors, we investigated alterations in cell cycle-related gene expression following HEK293 cell infection by using the Affymetrix U95A microarray. Serotype 3 reovirus infection results in differential expression of 10 genes classified as encoding proteins that function at the G(1)-to-S transition, 11 genes classified as encoding proteins that function at G(2)-to-M transition, and 4 genes classified as encoding proteins that function at the mitotic spindle checkpoint. Serotype 1 reovirus infection results in differential expression of four genes classified as encoding proteins that function at the G(1)-to-S transition and three genes classified as encoding proteins that function at G(2)-to-M transition but does not alter any genes classified as encoding proteins that function at the mitotic spindle checkpoint. We have previously shown that serotype 3, but not serotype 1, reovirus infection induces a G(2)-to-M transition arrest resulting from an inhibition of cdc2 kinase activity. Of the differentially expressed genes encoding proteins regulating the G(2)-to-M transition, chk1, wee1, and GADD45 are known to inhibit cdc2 kinase activity. A hypothetical model describing serotype 3 reovirus-induced inhibition of cdc2 kinase is presented, and reovirus-induced perturbations of the G(1)-to-S, G(2)-to-M, and mitotic spindle checkpoints are discussed.
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