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
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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.
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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.
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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.
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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.
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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.
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