RNA-seq analysis revealed that chloroquine(CQ) intervenes nephrotoxicity of nilotinib in an autophagy-independent manner
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ABSTRACT:
PROVIDER: PRJNA874052 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21230240_1.fastq.gz | Fastqsanger.gz | |||
| SRR21230240_2.fastq.gz | Fastqsanger.gz | |||
| SRR21230241_1.fastq.gz | Fastqsanger.gz | |||
| SRR21230241_2.fastq.gz | Fastqsanger.gz | |||
| SRR21230242_1.fastq.gz | Fastqsanger.gz |
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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.
2023-09-20 | GSE212122 | GEO
Project description:Pyronaridine (PN) and chloroquine (CQ) are structurally related anti-malarial drugs with primarily the same mode of action. However, PN is effective against several multidrug-resistant lines of Plasmodium falciparum, including CQ-resistant lines, suggestive of important operational differences between the two drugs. Synchronized trophozoite-stage cultures of P. falciparum strain K1 (CQ resistant) were exposed to 50% inhibitory concentrations (IC50) of PN and CQ, and parasites were harvested from culture after 4 and 24 hours exposure. Global transcriptional changes effected by drug treatment were investigated using DNA microarrays.
2011-08-02 | GSE30867 | GEO
Project description:Pyronaridine (PN) and chloroquine (CQ) are structurally related anti-malarial drugs with primarily the same mode of action. However, PN is effective against several multidrug-resistant lines of Plasmodium falciparum, including CQ-resistant lines, suggestive of important operational differences between the two drugs. Synchronized trophozoite-stage cultures of P. falciparum strain K1 (CQ resistant) were exposed to 50% inhibitory concentrations (IC50) of PN and CQ, and parasites were harvested from culture after 4 and 24 hours exposure. Global transcriptional changes effected by drug treatment were investigated using DNA microarrays. Plasmodium falciparum in vitro cultures were synchronized to trophozoite stage (22-24h post infection) and exposed to either CQ or PN at IC50 concentrations. 18 sample pairs (drug treated/untreated) were analyzed; 9 for CQ and 9 for PN. All drug-treated samples were labelled with Cy5 and untreated controls were labelled with Cy3.
2011-08-01 | E-GEOD-30867 | biostudies-arrayexpress
Project description:Chloroquine (CQ) could function as a lysosomotropic inhibitor to impair the autophagy-lysosome pathway, and is widely used to treat malarial, tumor and recently COVID-19. However, the effect of CQ treatment on porcine immature Sertoli cells (iSCs) remains unclear.;Here we showed that CQ treatment reduced iSCs viability in a dose-dependent manner. CQ treatment (20µM) of iSCs for 36h could elevate oxidative stress, damage mitochondrial function and promote apoptosis. Melatonin (MT) (10nM) could partially rescue CQ-induced phenotypic defects. Transcriptome profiling (RNA-seq) identified 1611 differentially expressed genes (DEGs) (776 up- and 835 down-regulated) (20µM CQ vs. DMSO control group), mainly involved in MAPK cascade, cell proliferation/apoptosis, HIF-1, PI3K-Akt and lysosome signaling pathways. In contrast, MT addition identified only 467 (224 up- and 243 down-regulated) DEGs (CQ+MT vs. DMSO), enriched in cell cycle, regulation of apoptotic process, lysosome and reproduction, respectively.Collectively, CQ treatment could impair porcine iSC viability by deranging apoptosis- and autophagy related signaling pathways, which could be partially rescued by MT supplementation.
2024-07-06 | GSE180995 | 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
Project description:Mutations in PfCRT confer chloroquine (CQ) resistance in P. falciparum. Point mutations in the homolog of the mammalian multidrug resistance gene (pfmdr1) can also modulate the levels of CQ response. However, parasites with the same pfcrt and pfmdr1 alleles exhibit a wide range of drug sensitivity, suggesting that additional genes contribute to levels of CQ resistance (CQR). We used 3 isogenic lines which have different drug resistance profiles corresponding to unique mutations in the pfcrt gene (106/1K76, 106/176I, and 106/76I-352K) to study changes in gene expression with and without CQ and genomic variations, i.e. copy number (CN) changes. RNA transcription levels from 45 genes were significantly altered in one or both mutants relative to the parent line. Of particular interest are genes encoding proteins involved in transport and/or regulation of cytoplasmic or compartmental pH, e.g. the V-type H+ pumping pyrophosphatase 2, Ca2+/H+ antiporter VCX1 and copy number changes in pfmdr1. A series of deletion (including 15 genes) also occurred at the beginning of chromosome 10. Keywords: low-dose 3h Chloroquine response, copy number variation
2008-06-26 | GSE10022 | 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. Gene expression modulations were measured in Huh7 harboring replicon cells stimulated with a 10M-BM-5M of a Chloroquine derivative compound called CQd, during 6h, 12h and 24h. Two independent experiments were performed at each time. An untreated control condition was performed in each experiment, expression was measured at the 24h time point. For the HCVcc model, gene expression analysis was analyzed in two conditions: infection and treatment of infected cells. To characterize modulations in time course of infection, Huh7 naM-CM-/ve cells were infected with JFH1/CS-N6-A4 viral stock and gene expression was measured at 6h, 24h and 48h postinfection. For each kinetic time point, an uninfected condition was performed and gene expression was measured. An additional control testing the interferon (IFN) induced modulations on infected cells was included and gene expression was measured after a 48h stimulation with 100 IU of IFN (alpha 2 b). To characterize the antiviral modulations resulting from treatment with Chloroquine (CQ) or a derivative compound (CQd), gene expression was measured in JFH1/CS-N6-A4 infected Huh7 cells treated with 40M-BM-5M of CQ or CQd during 12h or 48h post-treatment and infection. For each kinetic time point 12h and 48h, an untreated infected control was also performed and gene expression measured.
2012-06-30 | E-GEOD-30351 | biostudies-arrayexpress
Project description:Mutations in PfCRT confer chloroquine (CQ) resistance in P. falciparum. Point mutations in the homolog of the mammalian multidrug resistance gene (pfmdr1) can also modulate the levels of CQ response. However, parasites with the same pfcrt and pfmdr1 alleles exhibit a wide range of drug sensitivity, suggesting that additional genes contribute to levels of CQ resistance (CQR). We used 3 isogenic lines which have different drug resistance profiles corresponding to unique mutations in the pfcrt gene (106/1K76, 106/176I, and 106/76I-352K) to study changes in gene expression with and without CQ and genomic variations, i.e. copy number (CN) changes. RNA transcription levels from 45 genes were significantly altered in one or both mutants relative to the parent line. Of particular interest are genes encoding proteins involved in transport and/or regulation of cytoplasmic or compartmental pH, e.g. the V-type H+ pumping pyrophosphatase 2, Ca2+/H+ antiporter VCX1 and copy number changes in pfmdr1. A series of deletion (including 15 genes) also occurred at the beginning of chromosome 10. Experiment Overall Design: Three isogenic parasite lines were treated with and without 3h CQ and synchronized for total RNA extraction and hybridization to Affymetrix GeneChips® to study gene expression profiles. Genomic DNA from mixed culture was also extracted and hybridized to the same Affymetrix GeneChips. Total 18 total RNA samples (3 biological replicates per condition) and 6 genomic DNA samples (2 biological replicates per condition).
2008-11-06 | E-GEOD-10022 | biostudies-arrayexpress
Project description:Mesenchymal stromal cells (MSCs) can be utilized clinically for treatment of conditions that result from excessive inflammation. In a pro-inflammatory environment, MSCs adopt an anti-inflammatory phenotype resulting in immunomodulation. A sub-type of MSCs referred to as “marrow-isolated adult multilineage inducible” (MIAMI) cells, which were isolated from bone marrow, were utilized to show that the addition of autophagy modulators, tamoxifen (TX) or chloroquine (CQ), can alter how MIAMI cells respond to IFNg exposure in vitro resulting in an increased immunoregulatory capacity of the MIAMI cells. Molecularly, it was also shown that TX and CQ each alter both the levels of immunomodulatory genes and microRNAs which target such genes. However, the role of other non-coding RNAs (ncRNAs) such as long non-coding RNAs (lncRNAs) in regulating the response of MSCs to inflammation has been poorly studied. Here, we utilized transcriptomics and data mining to analyze the putative roles of various differentially regulated lncRNAs in MIAMI cells exposed to IFNg with (or without) TX or CQ. The aim of this study was to investigate how the addition of TX and CQ alters lncRNA levels and evaluate how such changes could alter previously observed TX- and CQ-driven changes to the immunomodulatory properties of MIAMI cells. Data analysis revealed 693 long intergenic non-coding RNAS (lincRNAs), 480 pseudogenes, and 642 antisense RNAs that were differentially regulated with IFNg, IFNg+TX and IFNg+CQ treatments. Further analysis of these RNA species based on the existing literature data revealed 6 antisense RNAs, 2 pseudogenes, and 5 lincRNAs that have the potential to modulate MIAMI cell’s response to IFNg treatment. Functional analysis of these genomic species based on current literature linking inflammatory response and ncRNAs indicated their potential for regulation of several key pro- and anti-inflammatory responses, including NFkB signaling, cytokine secretion and auto-immune responses. Overall, this work found potential involvement of multiple pro-and anti-inflammatory pathways and molecules in modulating MIAMI cells’ response to inflammation.
2022-03-31 | GSE197302 | GEO
Project description:Extracellular vesicles (EV) are signaling entities that are released by most, if not all, eukaryotic cells. EV are of special interest in cancer due to their reported roles in modulating the cancer microenvironment and facilitating invasion. Macroautophagy is a catabolic process initially known for the recycling of cytosolic cargos through lysosomal degradation, while its non-degradative functions have only begun to emerge. To better understand the relationships between autophagy machinery and small EV (sEV) biogenesis, we utilized chloroquine (CQ) to inhibit lysosomal degradation and autophagy turnover in triple-negative breast cancer (TNBC) cell lines and characterized its effects on sEV content and function. We performed quantitative mass spectrometry analysis of the sEV proteome, and discovered a CQ-induced enrichment of mammalian ATG8 paralogs and their adaptor proteins that coincided with increased levels of K48-specific polyubiquitination in sEV, as well as with the co-localization of ATG8s and endolysosomal markers in the cytoplasm. Using ATG4B knockout cells, we established the lipidation-dependent luminal localization of sEV-associated ATG8s. We demonstrated CQ-mediated enrichment of MAP1LC3B and GABARAP in CD63-high but not CD9-high sEV subpopulations. sEV isolated from CQ treated versus untreated cells had differential effects on recipient cell growth and HMEC-1 tube formation, suggesting sEV are an avenue of CQ mediated non-cell-autonomous biological effects. Our study demonstrates the flexibility of sEV composition in response to perturbation of intracellular trafficking pathways, and has implications for CQ efficacy in therapeutic settings.
2023-03-10 | PXD015614 | Pride