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PIAS3 induction of apoptosis in non-small cell lung cancer cells is p53-independent and has STAT3-independent mediator.

ABSTRACT: Protein inhibitor of activated STAT3 (PIAS3) is an endogenous inhibitor of STAT3 that negatively regulates STAT3 transcriptional activity and cell growth and demonstrates limited expression in the majority of human squamous cell carcinomas of the lung. In the present study we sought to determine if PIAS3 inhibits cell growth in non-small cell lung cancer (NSCLC) cell lines by induction of apoptosis and further determine the dependence of PIAS3 activity on p53 status by using both wild-type and p53-null cells. Our results demonstrate that over-expression of PIAS3 promotes caspase 3 activation and PARP cleavage. Furthermore, the expression of pro-survival family members Bcl-xL and Bcl-2 is decreased. These effects were observed after both transient and regulated expression of exogenous PIAS3 and were independent of p53 status. Furthermore, while p53 can promote apoptosis by inhibition of STAT3 activity, PIAS3 inhibition of STAT3 activity was also p53 independent. Microarray experiments were performed to further investigate the STAT3-dependence of PIAS3-induced apoptosis by comparing the apoptotic gene expression signature induced by PIAS3 over-expression with that induced by STAT3 siRNA. The results showed that a subset of apoptotic genes, including CIDEC and DAPK2, were uniquely expressed only after PIAS3 expression. Thus, PIAS3 may represent a promising lung cancer therapeutic target because of its p53-independent efficacy as well as its potential to synergize with direct STAT3 inhibitors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE42979 | GEO | 2012/12/19

SECONDARY ACCESSION(S): PRJNA184013

REPOSITORIES: GEO

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PIAS3 induction of apoptosis in non-small cell lung cancer cells is p53-independent and has STAT3-independent mediator.

Project description:Protein inhibitor of activated STAT3 (PIAS3) is an endogenous inhibitor of STAT3 that negatively regulates STAT3 transcriptional activity and cell growth and demonstrates limited expression in the majority of human squamous cell carcinomas of the lung. In the present study we sought to determine if PIAS3 inhibits cell growth in non-small cell lung cancer (NSCLC) cell lines by induction of apoptosis and further determine the dependence of PIAS3 activity on p53 status by using both wild-type and p53-null cells. Our results demonstrate that over-expression of PIAS3 promotes caspase 3 activation and PARP cleavage. Furthermore, the expression of pro-survival family members Bcl-xL and Bcl-2 is decreased. These effects were observed after both transient and regulated expression of exogenous PIAS3 and were independent of p53 status. Furthermore, while p53 can promote apoptosis by inhibition of STAT3 activity, PIAS3 inhibition of STAT3 activity was also p53 independent. Microarray experiments were performed to further investigate the STAT3-dependence of PIAS3-induced apoptosis by comparing the apoptotic gene expression signature induced by PIAS3 over-expression with that induced by STAT3 siRNA. The results showed that a subset of apoptotic genes, including CIDEC and DAPK2, were uniquely expressed only after PIAS3 expression. Thus, PIAS3 may represent a promising lung cancer therapeutic target because of its p53-independent efficacy as well as its potential to synergize with direct STAT3 inhibitors. The expression profiles of genes related to apoptosis in A549 cell line transfected with pCMV5 vector encoding human PIAS3 compared with that induced by STAT3 siRNA Cells in all three groups were grown in serum-free medium, then stimulated with EGF, then one group transfected with pCMV5 vector encoding human PIAS3, second group was induced by STAT3 siRNA, third group considered as control.

2012-12-19 | E-GEOD-42979 | biostudies-arrayexpress

Homo sapiens

Project description:PIAS3 induction of apoptosis in non-small cell lung cancer cells is p53-independent and has STAT3-independent mediator.

| PRJNA184013 | ENA

A Mesenchymal Tumor Cell State Confers Increased Dependency on the Bcl-xL Anti-apoptotic Protein in Kidney Cancer

Project description:Genome-wide genetic screens have identified cellular dependencies in many cancers. Using Novartis’ DRIVE and the Broad Institute’s Achilles shRNA screening datasets, we mined for targetable dependencies in kidney lineage cancer cells. Our studies identified a dependency, preferentially in kidney cancer cells versus cells of other lineages, on the BCL2L1 gene, which encodes the Bcl-xL anti-apoptotic protein. Genetic and pharmacological inactivation of Bcl-xL, but not its paralog BCL2, led to fitness defects in renal cancer cells, and also sensitized them to chemotherapeutics. Expression levels of Bcl-xL, VHL status, and p53 mutation status were insufficient to predict Bcl-xL dependence. Instead, analyzing the transcriptional hallmarks of response to Bcl-xL blockade identified an elevated mesenchymal cell state signature in Bcl-xL dependent lines. Functional studies to address if these cell state differences drive Bcl-xL dependence showed that maintaining mesenchymal characteristics was necessary to confer sensitivity to Bcl-xL loss; and, conversely, that promoting mesenchymal transition was sufficient to increase sensitivity to Bcl-xL inhibition in resistant cells. This mesenchymal signature was also observed in almost a third of human renal tumors, and is associated with worse clinical outcomes. Detachment from an organized epithelium incites protective apoptotic responses in normal cells (e.g. anoikis); however, our findings suggest that, in mesenchymal kidney cancer cells Bcl-xL activity counteracts this protective mechanism and enables tumor cell survival. Altogether, our studies uncover an unexpected link between cellular cell state and dependence on anti-apoptotic proteins, and justify the use of Bcl-xL blockade to target a clinically aggressive subset of human kidney cancers.

2022-06-15 | GSE173618 | GEO

MicroRNA expression data from Bcl-xL silenced A549 lung adenocarcinoma cells

Project description:Bcl-xL is an anti-apoptotic protein that is frequently found to be overexpressed in non-small cell lung cancer leading to an inhibition of apoptosis and poor prognosis. Recently, the role of miRNAs in regulating apoptosis and cell survival during tumorigenesis has become evident, with cancer cells showing perturbed expression of various miRNAs. We utilized miRNA microarrays to determine if miRNA dysregulation in bcl-xL silenced lung adenocarcinoma cells could be involved in regulating apoptotic behavior, and identified dysregulated miRNAs with putative targets involved in signal transduction pathways regulating apoptosis, cell proliferation and cell progression. Short interfering RNA-based transfection of A549 was carried out inducing a reduction in bcl-xL expression levels. 24 hours post-transfection total RNA was isolated using TRIzol reagent and hybridized onto Affymetrix GeneChip miRNA Arrays. A global miRNA expression profile was then established, which compared total RNA, extracted from siRNA-transfected and non-transfected A549 cells. All experiments were carried out with three independent biological replicates.

2013-05-18 | E-GEOD-47059 | biostudies-arrayexpress

E3 SUMO ligase PIAS3 fine-tunes dorsoventral patterning and visual response of cones in the mouse retina but is not essential for photoreceptor cell fate specification

Project description:Differentiation of distinct neurons in the developing retina is controlled by combinatorial action of a small subset of transcription factors and signalling molecules. Protein inhibitor of activated STAT3 (PIAS3) has been implicated in guiding the specification of both rod and cone photoreceptors through posttranslational modification of key retinal transcription factors. To investigate its role during retinal development, we deleted exon 2-5 of the mouse Pias3 gene, which resulted in complete loss of the PIAS3 protein. Pias3-/- mice did not exhibit any overt phenotype, and retinal lamination appeared normal by histology even at 18 months. We detected reduced photopic b-wave amplitude by electroretinography (ERG) analysis following green light stimulation of Pias3-/- retina at postnatal day (P) 21, suggesting a compromised visual response of medium wavelength (M) cones. No change was evident in response of short wavelength (S) cones or rod photoreceptors until 7 months. Immunohistochemistry demonstrated altered distribution of cone photoreceptors as revealed by increased S-opsin expression in the M-cone dominant dorsal retina. Transcriptome profiling of P21 and 18-month old Pias3-/- retina revealed aberrant expression of genes associated with photoreceptor function. Our studies suggest redundancy in SUMOylation-associated transcriptional control mechanisms and identify a specific though limited role of PIAS3 in modulating spatial patterning and optimal function of cone photoreceptor subtypes in the mouse retina.

2017-05-29 | GSE94011 | GEO

RNA-Sequencing analysis of BET inhibitor resistant cell lines

Project description:Targeting BET bromodomain proteins utilizing small molecules in an emerging anti-cancer strategy with clinical evaluation of at least six inhibitors now underway. While MYC downregulation was initially proposed as a key mechanistic property of BET inhibitors, recent evidence suggests that additional anti-tumor activities are important. Using the Eμ-Myc model of B-cell lymphoma we demonstrate that BET inhibition with JQ1 is a potent inducer of p53-independent apoptosis that occurs in the absence of effects on Myc gene expression. JQ1 skews the expression of pro-apoptotic (Bim) and anti-apoptotic (BCL-2/BCL-xL) BCL-2 family members to directly engage the mitochondrial apoptotic pathway. Consistent with this, Bim knockout or Bcl-2 overexpression inhibited apoptosis induction by JQ1. We identified lymphomas that were either intrinsically resistant to JQ1-mediated death or acquired resistance following in vivo exposure. Strikingly, in both instances BCL-2 was strongly upregulated and was concomitant with activation of RAS pathways. Eμ-Myc lymphomas engineered to express activated Nras upregulated BCL-2 and acquired a JQ1-resistance phenotype. These studies provide important information on mechanisms apoptosis induction and resistance to BET-inhibition, while providing further rationale for the translation of BET inhibitors in aggressive B-cell lymphomas.

2016-09-18 | GSE87050 | GEO

Engineering ABT-737 Resistance in MYC-driven Lymphomas Identifies DHX9 as a Drug Response Modifier

Project description:Many traditional cytotoxic agents used in the treatment of cancer function by eliciting an apoptotic response in tumor cells. However, evasion of apoptosis by BCL-2 family members is often deregulated prior to therapeutic intervention leading to treatment failure. To address this, ABT-737 was rationally designed to target BCL-2-like family members and has shown promising results against tumor cells dependent on BCL-2 for their survival. One shortcoming is that MCL-1, a member of the BCL-2 family is poorly inhibited by ABT-737 and is a major cause of resistance. To gain insight into biological pathways that could circumvent this resistance, we designed an shRNA screen to identify novel sensitizers to ABT-737 by engineering MYC driven lymphomas that were resistant to ABT-737 due to endogenous MCL-1 expression. Utilizing this model, we performed a shRNA drop-out screen and identified Dhx9 as a target whose suppression sensitizes cells to ABT-737. DHX9 loss lead to replicative stress signaling, which in turn potently induced the BH3-only proteins, NOXA and PUMA, in a p53-dependent manner to curtail MCL-1 activity. Induction of NOXA is essential for ABT-737 sensitization. Our results ascribe a novel role for DHX9 in the replicative stress pathway and link DHX9 activity to p53 function in vivo. Comparison of Arf-/-Eu-myc/Bcl-2 lymphomas expressing either control Rluc.713 or Dhx9 shRNA, Dhx9.1241

2013-04-03 | E-GEOD-36938 | biostudies-arrayexpress

MicroRNA expression data from Bcl-xL silenced A549 lung adenocarcinoma cells

2013-05-18 | GSE47059 | GEO

Transcription profiling of mouse pulmonary Alveolar Type II Cells deleted for Stat2

Project description:Deletion of Stat3 induced genes influencing protein metabolism, transport, chemotaxis and apoptosis and decreased the expression of genes mediating lipid synthesis and metabolism. Srebf1 and 2, key regulators of fatty acid and steroid biosynthesis, were decreased in Stat3D/D mice. Stat3 influenced both pro- and anti-apoptotic pathways, regulating and maintaining the balance between a subset of pro- and anti-apoptotic genes that determine cell death or survival. Akt, a known target of Stat3, participates in many Stat3 mediated pathways including Jak-Stat signaling, apoptosis, the MAPK signaling, cholesterol and fatty acid biosynthesis. Deletion of Stat3 from type II epithelial cells altered the expression of genes regulating diverse cellular processes, including cell growth and apoptosis, lipid biosynthesis and metabolism. Stat3 regulates cell formation through a complex regulatory network that likely enhances alveolar epithelial cell survival and surfactant/lipid synthesis, necessary for the protection of the lung during injury. Experiment Overall Design: To better understand the roles and molecular mechanisms by which Stat3 influences gene expression in lung, the effect of cell-selective deletion of Stat3 (Stat3D/D) on genome wide mRNA expression profiles was determined in murine type II alveolar epithelial cells. Differentially expressed genes were identified from Affymetrix Murine GeneChips analysis and subjected to gene ontology classification promoter analysis, pathway mapping and literature mining.

2008-06-15 | E-GEOD-6846 | biostudies-arrayexpress

Transcription profiling of human lymphocyte response to E. coli to identify any transcriptional component to the protection in vitro bacterially induced PBMC apoptosis

Project description:Sepsis induces lymphocyte apoptosis which can be prevented by over-expression of anti-apoptotic Bcl-2 family members. The anti-apoptotic activity of Bcl-2 family members is localized in the BH4 domain. The therapeutic peptide, TAT-BH4, was found to prevent sepsis-induced lymphocyte apoptosis in vivo. We also showed that this peptide prevents PBMC apoptosis in response to bacterial exudate. Here we studied whether there was a transcriptional component to that protection in vitro in bacterially-induced PBMC apoptosis.

2006-02-07 | E-MEXP-555 | biostudies-arrayexpress

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