Transcriptomic analysis to identify genes associated with chloroquine-mediated radiosensitization of glioblastoma stem cells
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PROVIDER: PRJNA934324 | ENA |
REPOSITORIES: ENA
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Project description:Tumour suppressor p53 regulates hundreds of genes by either activating or repressing their transcription. p53-dependent transcription is activated by stress factors such as DNA damage, reactive oxygen species, hypoxia or oncogenic signaling. Lysosomotropic agent and DNA intercalating agent chloroquine has been implicated in sensitizing glioblastoma to radiation via p53 pathway. This study evaluates the effects of chloroquine in glioblastoma stem cells differing for the status of TP53 by using an integrated approach encompassing in vitro, in vivo and in silico methodologies to characterize the impacts of chloroquine on cell vitality, tumor-propagating capacity and gene expression. We used microarrays to identify the genes whose expression is influenced by DNA intercalator chloroquine (ClQ) in glioblastoma stem cells expressing wild type p53 (line #993), mutant p53 (line G112) or a p53 null line #1095. To compare chloroquine-associated transcriptomic changes with those induced by ionizing radiation (IR), samples of IR-treated line #993 ("#993_IR") were analyzed in parallel with ClQ-treated samples ("993_ClQ").
2023-08-04 | GSE225191 | GEO
Project description:ITDR MS-CETSA was conducted on chloroquine-treated live parasites and lysate of P. falciparum trophozoites in order to identify potential drug protein targets.
2023-12-11 | PXD046662 | Pride
Project description:Anti-malaria drug chloroquine has been used as an anti-inflammatory agent for treating systemic lupus erythematosus and rheumatoid arthritis, without clear mechanism of action. Here we report that chloroquine potently inhibits the expression of proinflammatory cytokines through transrepression of glucocorticoid receptor (GR). Instead of direct binding to GR, chloroquine synergistically activates glucocorticoid signaling via inhibition of lysosomal functions. In mouse collagen induced arthritis model, chloroquine synergizes the therapeutic effects of glucocorticoid. Lysosomal inhibition by bafilomycin A1, an inhibitor of V-type ATPase, or by knockdown of transcription factor EB (TFEB), a master activator of lysosomal biogenesis, mimics the effects of chloroquine. These results reveal an unexpected regulation of glucocorticoid signaling by lysosomes and provide a mechanistic basis for treating inflammation and autoimmune diseases by combination of glucocorticoids and lysosomal inhibitors.
2012-01-18 | GSE24579 | GEO
Project description:Anti-malaria drug chloroquine has been used as an anti-inflammatory agent for treating systemic lupus erythematosus and rheumatoid arthritis, without clear mechanism of action. Here we report that chloroquine potently inhibits the expression of proinflammatory cytokines through transrepression of glucocorticoid receptor (GR). Instead of direct binding to GR, chloroquine synergistically activates glucocorticoid signaling via inhibition of lysosomal functions. In mouse collagen induced arthritis model, chloroquine synergizes the therapeutic effects of glucocorticoid. Lysosomal inhibition by bafilomycin A1, an inhibitor of V-type ATPase, or by knockdown of transcription factor EB (TFEB), a master activator of lysosomal biogenesis, mimics the effects of chloroquine. These results reveal an unexpected regulation of glucocorticoid signaling by lysosomes and provide a mechanistic basis for treating inflammation and autoimmune diseases by combination of glucocorticoids and lysosomal inhibitors. Macrophage THP-1 cells treated with LPS, chloroquine and dexamethasone.
2012-01-18 | E-GEOD-24579 | biostudies-arrayexpress
Project description:Cell-Free Plasma MicroRNAs that Identify Patients with Glioblastoma
| PRJNA764727 | ENA
Project description:Ribosome biogenesis has emerged as a potential target for cancer therapy. We have characterize a new biological activity of the antimalarial drug amodiaquine as a inhibitor of ribosome biogenesis. Interestingly, amodiaquine retains the autophagy inhibitory activity of its analog chloroquine, but in addition, displays properties of the ribosome biogenesis inhibitor BMH-21. We performed a RNAseq analysis to identify shared and unique mechanisms of action among these drugs. Gene expression was profiled in U2OS cell line, using 24 samples divided in 4 treatment groups: Untreated, Amodiaquine, Chloroquine and BMH-21, incubated with compounds for 12 hours.
2019-09-01 | E-MTAB-7616 | biostudies-arrayexpress
Project description:Hypoxia is negatively associated with glioblastoma patient survival and contributes strongly to tumor resistance. Unfortunately novel anti-angiogenic therapy increases hypoxia and activates survival pathways in tumor cells leading to inevitable tumor relapse. Here we demonstrate that primary glioma cultures and cell lines depend on autophagy to survive severe hypoxia but also at normal oxygen levels. Positive regulators of autophagy are expressed at higher levels in tumor cells and induction in severe hypoxia is more prominent compared to normal brain cells. We demonstrate that autophagy is an essential/critical target for novel treatment in glioblastoma. We show ATG9A is induced by severe hypoxia and could be a novel player of the autophagic response in glioma cells. ATG9A targeting inhibited tumor growth, suggesting an essential role in glioma cell survival in vivo. While autophagy induction was also observed in normal astrocytes, glioma cells displayed a higher sensitivity towards autophagy inhibitors. Importantly, patient-derived cultures exhibited varying sensitivity towards anti-autophagy treatment, where certain cultures were dependent on autophagy already in normoxic conditions. The treatment of tumor bearing mice with the autophagy inhibitor chloroquine significantly increased mice survival, but combination treatment of the agent with bevacizumab did not reveal additive or synergistic effect. The present study demonstrates that inhibition of autophagy using chloroquine as a single agent provides a novel treatment strategy against glioblastoma. It remains to be seen whether autophagy inhibition will improve current standard of care treatment of newly diagnosed glioblastoma patients and whether more specific inhibitors will lead to stronger therapeutic outcome. (Provisional)
2015-11-10 | E-MTAB-3085 | biostudies-arrayexpress
Project description:This retrospective multicenter pilot study aims to determine potential cell-free microRNAs (cfmiRs) that identify patients with primary GBM (pGBM) tumors and to monitor Glioblastoma (GBM) recurrence.
2023-05-26 | GSE184472 | GEO
Project description:Through transcriptome sequencing, it was determined that AMPK is a key pathway involved in the radiosensitization effect of nab-paclitaxel, and its sensitization effect may be attributed to ZMAT3 and NF- κB signaling pathway is closely related.
2024-06-01 | GSE262746 | GEO
Project description:The main goal of this study is to characterize the transcriptional modulations induced by antiviral compounds derived from chloroquine on Huh7 cells infected with HCV. And thus to identify among the genes modulated by infection, those who are regulated by chloroquine and potentially involved in the antiviral activity of the compound.Two HCV cell models were used: a non-infectious HCV replicon and the infectious HCV cell culture (HCVcc). In addition, this study aimed to highlight the characteristics of derivatives of antiviral chloroquine, compared with chloroquine itself. Abstract from the associated publication: Autophagy is a process of self-degradation of cellular components in which double-membrane autophagosomes sequester organelles or portion of cytosol and fuse with lysosomes or vacuoles for breakdown by resident hydrolases. Autophagy is upregulated in response to extra- or intracellular stress and signals such as starvation, growth factor deprivation, ER stress, and pathogen infection. Indeed, infection with hepatitis C virus (HCV) was shown to induce autophagy through ER stress signaling and subsequent Unfolded Protein Response (UPR) activation. Moreover, a role of autophagy in promoting HCV infection has been suggested and chloroquine (CQ), a lysosomal protease inhibitor, has been seen blocking autophagy as well as inhibiting HCV replication. In the present report, mechanisms accounting for these inhibitory effects were investigated. Gene expression profiling was performed on CQ treated JFH-1-infected Huh7 cells to identify the host cellular genes that are transcriptionally regulated by infection, and silenced by CQ-based treatment. Herein, we demonstrate that CQ reduces the expression of genes induced by the viral infection such as those encoding autophagic key factors triggering the turn-off of mTOR activity as well as factors involved in p53 and NF-KappaB activities. However, we present several lines of evidence demonstrating that the CQ repressive effect observed on the HCV-induced pathways results from a decrease of ER stress due to the upstream pH-dependent inhibitory effect of CQ on viral replication.
2012-07-01 | GSE30351 | GEO