MicroRNA expression data from Bcl-xL silenced A549 lung adenocarcinoma cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Norahayu Othman
PROVIDER: E-GEOD-47059 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
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.
2013-05-18 | GSE47059 | GEO
Project description:Kruppel-like transcription factor (KLF)13, previously shown to regulate RANTES expression in vitro, is a member of the Kruppel- like family of transcription factors that controls many growth and developmental processes. To ascertain the function of KLF13 in vivo, Klf13-deficient mice were generated by gene targeting. As expected, activated T lymphocytes from Klf13-/- mice show decreased RANTES expression. However, these mice also exhibit enlarged thymi and spleens. TUNEL, as well as spontaneous and activation-induced death assays, demonstrated that prolonged survival of Klf13-/- thymocytes was due to decreased apoptosis. Microarray analysis suggests that protection from apoptosis-inducing stimuli in Klf13-/- thymocytes is due in part to increased expression of BCL-XL, a potent antiapoptotic factor. This finding was confirmed in splenocytes and total thymocytes by real-time quantitative PCR and Western blot as well as in CD4+CD8? single-positive thymocytes by real-time quantitative PCR. Furthermore, EMSA and luciferase reporter assays demonstrated that KLF13 binds to multiple sites within the Bcl-XL promoter and results in decreased Bcl-XL promoter activity, making KLF13 a negative regulator of BCL-XL.
2007-05-11 | E-SMDB-4035 | biostudies-arrayexpress
Project description:Nilotinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor for the first-line treatment of Philadelphia chromosome-positive chronic myeloid leukemia. However, its nephrotoxicity has become prominent with the increase of clinical use, which greatly limits its long-term application. So far, the mechanism of nilotinib’s nephrotoxicity is still unknown leading to a lack of clinical intervention strategies. Here, we found that nilotinib could promote intrinsic apoptosis of both vascular endothelial cells and renal tubular epithelial cells, which was mediated by the excessive ubiquitin-proteasome degradation of anti-apoptotic protein BCL-XL. Moreover, we confirmed that Chloroquine (CQ) could intervene nilotinib-induced apoptosis by reversing the decreased BCL-XL whose mechanism was not relied on autophagy inhibition. Furthermore, RNA-seq analysis was applied to identify the potential target of CQ and the result suggested that CQ could alleviate nilotinib-induced ANKRD1 reduction. Further, we found ANKRD1 abrogated cell apoptosis by preventing ubiquitination of BCL-XL and hence inhibiting BCL-XL degradation. In conclusion, our research reveals the molecular mechanism of nilotinib’s nephrotoxicity, wherein the excessive degradation of BCL-XL via ubiquitin-proteasome pathway promotes kidney cells apoptosis, and provides CQ analogs as the clinical intervention strategy of nilotinib’s nephrotoxicity whose pharmacological effect is dependent on ANKRD1 instead of autophagy inhibition.
2023-09-20 | GSE212122 | GEO
Project description:The heterogeneous therapy response observed in colorectal cancer is in part due to cancer stem cells (CSCs) that resist chemotherapeutic insults. The anti-apoptotic protein BCL-XL plays a critical role in protecting CSCs from cell death, where its inhibition with high doses of BH3-mimetics can induce apoptosis. To identify pathways that can regulate sensitivity to BCL-XL inhibition, we screened a compound library for synergy with low dose BCL-XL inhibitor A-1155463 and reveal that FGFR4 inhibition effectively sensitizes to A-1155463 both in vitro and in vivo. Mechanistically, we identify a rescue response that is activated upon BCL-XL inhibition and leads to rapid FGF2 secretion and subsequent FGFR4-mediated post-translational stabilization of MCL-1. FGFR4 inhibition prevents MCL-1 upregulation and thereby sensitizes CSCs to BCL-XL inhibition. Altogether, our findings suggest a cell transferable induction of a FGF2/FGFR4 rescue response in CRC that is induced upon BCL-XL inhibition and leads to MCL-1 upregulation.
2021-12-22 | GSE159504 | GEO
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
Project description:RNA expression analysis was performed to compare patterns to sensitivity to BCL2 inhibitors (ABT-263). Overexpression of the prosurvival Bcl-2 family members (Bcl-2, Bcl-xL and Mcl-1) is commonly associated with tumor maintenance, progression and chemoresistance. We previously reported the discovery of ABT-737, a potent, small molecule Bcl-2 family protein inhibitor. A major limitation of ABT-737 is that it is not orally bioavailable. This may limit its use for chronic single agent treatment and the flexibility to dose in combination with parenteral chemotherapy. Here we report the discovery and biological properties of ABT-263, a potent, orally bioavailable Bad-like BH3 mimetic (Kiâ??s of < 1 nM for Bcl-2, Bcl-xL and Bcl-w). The oral bioavailability of ABT-263 in preclinical animal models is 20% - 50%, depending on formulation. ABT-263 disrupts Bcl-2/Bcl-xL interactions with pro-death proteins (e.g., Bim) in cells leading to the initiation of apoptosis within 2 hr post-treatment. In human tumor cells, ABT-263 rapidly induces Bax translocation, cytochrome c release and subsequent programmed cell death. Oral administration of ABT-263 alone induces complete tumor regressions in xenograft models of small cell lung cancer and acute lymphoblastic leukemia. In xenograft models of aggressive B-cell lymphoma and multiple myeloma where ABT-263 exhibits modest or no single agent activity, it significantly enhances the efficacy of clinically relevant therapeutic regimens. These data provide the rationale for clinical trials evaluating ABT-263 in SCLC and B-cell malignancies. The oral efficacy of ABT-263 should provide dosing flexibility to maximize clinical utility as both a single agent and in combination with standard chemotherapeutic regimens. Experiment Overall Design: Naive cell lines were isolated in duplicate or triplicate (only a single for H69AR) to determine RNA expression pattern.
2008-06-19 | E-GEOD-10841 | biostudies-arrayexpress
Project description:Oncogene-driven lung cancers such as those with activating mutations in the epidermal growth factor receptor (EGFR) often harbor additional co-occurring genetic alterations. The significance of most alterations co-occurring with mutant EGFR remains unclear. We report the impact of loss of the mRNA splicing factor RBM10 in human EGFR mutant lung cancer. RBM10 loss decreased EGFR inhibitor efficacy in patient-derived EGFR mutant tumor models. RBM10 regulated mRNA splicing of the mitochondrial apoptotic regulator Bcl-x. Genetic inactivation of RBM10 diminished EGFR inhibitor-mediated apoptosis by altering Bcl-x splicing, decreasing Bcl-xS (pro-apoptotic) and increasing Bcl-xL (anti-apoptotic) levels. Co-inhibition of Bcl-xL and mutant EGFR overcomes resistance induced by RBM10 loss. RBM10 loss was a biomarker of poor response to EGFR inhibitor treatment in clinical samples. Inactivation of the splicing factor RBM10 is a key co-occurring genetic alteration in EGFR mutant tumors that limits EGFR inhibitor efficacy and a potential biomarker of Bcl-xL inhibitor response.
2022-06-04 | GSE199240 | GEO
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
Project description:Radiotherapy has a critical role in the treatment of small cell lung cancer (SCLC). Effectiveness of radiation in SCLC remains limited as resistance results from defects in apoptosis. In the current study, we investigated whether using a Bcl-2/Bcl-XL inhibitor S44563 can enhance radiosensitivity of SCLC cells in vitro and in vivo. In vitro studies confirmed that S44563 induce apoptosis in SCLC cells by inducing hallmarks of apoptosis (cleaved caspase-3, sub-G1 fraction induction and induction of the mitochondrial caspase activation pathway). S44563 markedly enhanced sensitivity of H146 cells and H69 cells to radiation in clonogenic assay. In addition, the combination S44563 and cisplatin-based chemo-radiation showed a dramatic tumor growth delay and increased overall survival in mouse xenograft models. In vitro experiments demonstrated a greater induction of apoptosis (sub-G1 fraction and cleaved caspase-3) with the combination as well as in vivo caspase-3 immunostaining. This positive interaction between S44563 and radiation was greater when S44563 was given after the completion of the radiation, which may be explained by the radiation-induced over expression of anti-apoptotic proteins (Bcl-2 and Bcl-XL) through the NF-?B pathway activation. Taken together, these data underline the critical role of sequence administration of targeted therapies with conventional therapies. SCLC cells which survive to IR highly rely on the induction of anti apoptotic proteins in part through NF- ?B activation for their survival yielding to the concept of 'contextual oncogene addiction' to the Bcl-2/Bcl-XL pathway providing rational for targeting survival pathways to potentiate IR. For transcriptome analysis, 106 cells were seeded in T25 flasks, allowed to growth for 24 h, and then left untreated or treated with 2 Gy radiation. After 24 hours, cells were harvested, lysed for the extraction of RNA, and processed to analyze gene expression.The design of this study consists to 6 hybridizations in dual color with Agilent Human Genome 4x44K (design 014850). The reference is always the untreated condition.
2013-02-01 | E-MTAB-966 | biostudies-arrayexpress
Project description:Kruppel-like transcription factor (KLF)13, previously shown to regulate RANTES expression in vitro, is a member of the Kruppel- like family of transcription factors that controls many growth and developmental processes. To ascertain the function of KLF13 in vivo, Klf13-deficient mice were generated by gene targeting. As expected, activated T lymphocytes from Klf13-/- mice show decreased RANTES expression. However, these mice also exhibit enlarged thymi and spleens. TUNEL, as well as spontaneous and activation-induced death assays, demonstrated that prolonged survival of Klf13-/- thymocytes was due to decreased apoptosis. Microarray analysis suggests that protection from apoptosis-inducing stimuli in Klf13-/- thymocytes is due in part to increased expression of BCL-XL, a potent antiapoptotic factor. This finding was confirmed in splenocytes and total thymocytes by real-time quantitative PCR and Western blot as well as in CD4+CD8? single-positive thymocytes by real-time quantitative PCR. Furthermore, EMSA and luciferase reporter assays demonstrated that KLF13 binds to multiple sites within the Bcl-XL promoter and results in decreased Bcl-XL promoter activity, making KLF13 a negative regulator of BCL-XL. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Keywords: Logical Set
2007-07-17 | GSE8497 | GEO