Axitinib exposure triggers endothelial cells senescence through ROS accumulation and ATM activation
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ABSTRACT:
PROVIDER: PRJNA521866 | ENA |
REPOSITORIES: ENA
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Project description:Here we report that Axitinib, an inhibitor of VEGFRs currently in use as a second line treatment for advanced renal cell carcinoma, promotes senescence of human endothelial cells in vitro. Mechanistically, this requires oxidative stress-dependent activation of the Ataxia Telangiectasia Mutated (ATM) kinase. Induction of oxidative stress-related genes distinguishes the response of endothelial cells to Axitinib from that to doxorubicin
2019-07-02 | GSE126426 | GEO
Project description:<p>Cellular senescence affects many physiological and pathological processes and is characterized by durable cell cycle arrest, an inflammatory secretory phenotype and metabolic reprogramming. Here, by using dynamic transcriptome and metabolome profiling in human fibroblasts with different subtypes of senescence, we show that a homeostatic switch which results in glycerol-3-phosphate (G3P) and phosphoethanolamine (PEtn) accumulation links lipid metabolism to the senescence gene expression program. Mechanistically, p53-dependent glycerol kinase (GK) activation and post-translational inactivation of Phosphate Cytidylyltransferase 2-Ethanolamine (PCYT2) regulate this metabolic switch, which promotes triglyceride accumulation in lipid droplets and induces the senescence gene expression program. Conversely, G3P phosphatase (G3PP) and Ethanolamine-Phosphate Phospho-Lyase (ETNPPL)-based scavenging of G3P and PEtn acts in a senomorphic way by reducing G3P and PEtn accumulation. Collectively, our study ties G3P and PEtn accumulation to controlling lipid droplet biogenesis and phospholipid flux in senescent cells, providing a potential therapeutic avenue for targeting senescence and related pathophysiology.</p>
2024-01-09 | MTBLS7118 | MetaboLights
Project description:We found histological evidence for increased abundance of iron accumulating cells in association with fibrotic lung, kidney, and heart diseases in mice and humans. We showed that inducing iron accumulation by intratracheal iron delivery in mice is a potent inducer of inflammation, cellular senescence, and fibrosis. The aim of this study has been to understand the single cell dynamics of iron accumulation and the mechanics that link it to in vivo senescence and to fibrogenesis. To get deeper insight into how different cell types respond to iron accumulation, we performed single nuclei RNA sequencing (snRNA-seq) of lungs from mice which received a single intratracheal dose of iron 2 or 6 days prior to analysis, or PBS 6days prior to analysis (control).
2023-08-18 | E-MTAB-13032 | biostudies-arrayexpress
Project description:The ATM protein kinase is a master regulator of the DNA damage response and also an important sensor of oxidative stress in mammals. Loss of ATM or its ability to be activated by reactive oxygen species (ROS) generates high levels of ROS and an excess of single-strand DNA breaks in non-dividing human cells. Here we map locations of poly-ADP-ribose and RNA-DNA hybrid accumulation genome-wide in post-mitotic human neurons with ATM inhibition and find that these locations are coincident with promoter regions, active transcription histone marks, and sequences with high GC content. Antioxidant treatment reverses the accumulation of R-loops in transcribed regions, consistent with the central role of ROS in promoting these lesions. In A-T patient cerebellum tissue, RNAseq analyses show large-scale transcriptional changes that correlate with both expression level and GC content of transcribed genes. Based on these results we postulate that transcription-associated lesions accumulate in ATM-deficient neurons and that the single-strand breaks and PARylation at these sites ultimately generate changes in transcription that compromise cerebellum function and lead to neurodegeneration of this tissue over time in A-T patients.
2024-03-01 | GSE233479 | GEO
Project description:G-quadruplex ligands (G4L) exert their anti-proliferative effect through telomere-dependent and -independent mechanisms, but the inter-relationship between autophagy, cell growth arrest and cell death induced by these ligands remains largely unexplored. 20A is a 2,4,6-triarylpyridine derivative that binds to G4-DNA with fair to excellent selectivity. Here, we demonstrate that this compound impairs cancer cell viability through induction of senescence and apoptotic cell death in a p53-independent manner. In vivo results corroborate those obtained in in vitro, showing that 20A elicits an important tumor growth inhibition in HeLa-xenografted tumor model. The transcriptomic and proteomic analyses reveal the functional enrichment in the growth arrest, DDR and lysosomal pathways upon 20A treatment. More particularly, we find that ATM and autophagy are activated upon 20A treatment. Genetic inhibition of ATM following 20A treatment inhibits both autophagy and senescence and directs cells to apoptosis. Moreover, loss of autophagy by deletion of two essential autophagy genes ATG5 and ATG7 leads to failure of CHK1 activation and increased cell death triggered by 20A. Our results therefore identify ATM as a critical determinant in the balance between senescence and apoptosis and uncover autophagy as one of the key mediators of such regulation. Thus, targeting the ATM/autophagy pathway might be a promising strategy to achieve the maximal therapeutic effect of the 20A G4-ligand.
2019-02-19 | PXD009430 | Pride
Project description:G-quadruplex ligands (G4L) exert their anti-proliferative effect through telomere-dependent and -independent mechanisms, but the inter-relationship between autophagy, cell growth arrest and cell death induced by these ligands remains largely unexplored. 20A is a 2,4,6-triarylpyridine derivative that binds to G4-DNA with fair to excellent selectivity. Here, we demonstrate that this compound impairs cancer cell viability through induction of senescence and apoptotic cell death in a p53-independent manner. In vivo results corroborate those obtained in in vitro, showing that 20A elicits an important tumor growth inhibition in HeLa-xenografted tumor model. The transcriptomic and proteomic analyses reveal the functional enrichment in the growth arrest, DDR and lysosomal pathways upon 20A treatment. More particularly, we find that ATM and autophagy are activated upon 20A treatment. Genetic inhibition of ATM following 20A treatment inhibits both autophagy and senescence and directs cells to apoptosis. Moreover, loss of autophagy by deletion of two essential autophagy genes ATG5 and ATG7 leads to failure of CHK1 activation and increased cell death triggered by 20A. Our results therefore identify ATM as a critical determinant in the balance between senescence and apoptosis and uncover autophagy as one of the key mediators of such regulation. Thus, targeting the ATM/autophagy pathway might be a promising strategy to achieve the maximal therapeutic effect of the 20A G4-ligand.
2019-04-17 | GSE113424 | GEO
Project description:Nutrient deprivation triggers the release of signal-sequence-lacking antioxidant superoxide dismutase 1 (SOD1). We now report that secreted SOD1 is functionally active and accompanied by export of other antioxidant enzymes such as thioredoxins, (Trx1 and Trx2) and peroxiredoxin Ahp1. Our data reveal that starvation increases mitochondrial activity, which generates higher, but non-toxic, levels of reactive oxygen species (ROS). Inhibiting mitochondrial activity or ROS prevents antioxidants secretion. We suggest that in response to ROS production that can permeate the plasma membrane, the cells respond by secreting antioxidants to prevent ROS-mediated damage in the extracellular space. These findings provide an understanding of why cells secrete signal sequence lacking antioxidant enzymes in response to starvation.
2020-03-26 | PXD016815 | Pride
Project description:ATM (ataxia-telangiectasia mutated) protein plays a central role in phosphorylating a network of proteins in response to DNA double strand breaks. These phosphorylated proteins function in signalling pathways designed to maintain the stability of the genome and minimize the risk of disease by controlling cell cycle checkpoints, initiating DNA repair and regulating gene expression. We employed a modified TiSH global quantitative phosphoproteomics approach to identify cytoplasmic proteins altered in their phosphorylation state in control and A-T cells in response to oxidative damage. We demonstrated that ATM was activated by oxidative damage in the cytoplasm as well as in the nucleus and identified a total of 9,612 phosphorylation sites including 6,650 high confidence sites mapping to 2,536 unique proteins.
2016-01-04 | PXD002850 | Pride
Project description:Leaf senescence is a highly coordinated and complicated process with the integration of numerous internal and environmental signals. Salicylic acid (SA) and reactive oxygen species (ROS) are two well-defined inducers of leaf senescence, whose contents progressively and inter-dependently increase during leaf senescence via a yet unknown mechanism. Here, we have characterized a newly identified positive regulator of leaf senescence, WRKY75, and demonstrated that knock-down or knock-out of WRKY75 delays, while over-expression of WRKY75 accelerates age-dependent leaf senescence. The WRKY75 transcription is induced by age, SA, H2O2, as well as multiple plant hormones. Meanwhile, WRKY75 is able to promote SA production by inducing the transcription of SA INDUCTION-DEFICIENT 2 (SID2), and suppress H2O2 scavenging partly by repressing the transcription of CATALASE 2 (CAT2). Genetic analysis reveals that the SID2 mutation or an increase of catalase activity rescues the precocious leaf senescence phenotype evoked by WRKY75 over-expression. Based on these results, we propose a “tripartite amplification loop” model in which WRKY75, SA and ROS undergo a gradual but self-sustained rise driven by three interlinked positive feedback regulations. This tripartite amplification loop provides a molecular framework connecting the upstream signals, such as age, ethylene, JA and ABA, to the downstream regulatory network executed by those SA-responsive and H2O2-responsive transcription factors during leaf senescence.
2017-11-07 | GSE102302 | GEO
Project description:The downstream events and target genes of p53 in senescence responses are not fully understood. Here, we report a novel function of the forkhead transcription factor Foxp3, a key player in mediating T cell inhibitory function, in p53-mediated cellular senescence. Overexpression of Foxp3 in mouse embryonic fibroblasts (MEFs) accelerates senescence, whereas Foxp3 knockdown leads to escape from p53-mediated senescence in p53-expressing MEFs. Consistently, Foxp3 expression resulted in the induction of senescence in epithelial cancer cells, including MCF7 and HCT116. Foxp3 overexpression also increased the intracellular levels of reactive oxygen species (ROS). The ROS inhibitor N-acetyl-L-cysteine rescued Foxp3 expression-induced senescence. Furthermore, the elevated ROS levels that accompanied Foxp3 overexpression were paralleled by an increase in p21 expression. Knockdown of p21 in Foxp3-expressing MEFs abrogated the Foxp3-dependent increase in ROS levels, indicating that Foxp3 acts through p21 induction and subsequent ROS elevation to trigger senescence. Collectively, these results suggest that Foxp3 is a downstream target of p53 that is sufficient to induce p21 expression and ROS production and is necessary for p53-mediated senescence. control and treated samples (human), young passage (p3) or old passage (p7) samples (mouse)
2015-08-13 | E-GEOD-71980 | biostudies-arrayexpress