Doxorubicin induces the senescence-associated secretion phenotype in RAW264.7 cells
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ABSTRACT:
PROVIDER: PRJNA1228637 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32499278_1.fastq.gz | Fastqsanger.gz | |||
| SRR32499278_2.fastq.gz | Fastqsanger.gz | |||
| SRR32499279_1.fastq.gz | Fastqsanger.gz | |||
| SRR32499279_2.fastq.gz | Fastqsanger.gz | |||
| SRR32499280_1.fastq.gz | Fastqsanger.gz |
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Project description:Doxorubicin is a widely used anti-cancer drug, and its toxicological effects on healthy tissues, especially the heart, remains challenging in therapy. To explore the potential targets that ameliorate doxorubicin-induced cardiotoxicity (DIC), we aimed to investigate the role that macrophages play in the DIC development. Senescence of RAW264.7 cells was induced through doxorubicin administration in the experiment, and the transcription of secretory components was analyzed in this study.
2025-03-03 | GSE290573 | GEO
Project description:A major aging hallmark is the accumulation of cellular senescence burden. Over time senescent cells contribute to tissue deterioration through chronic inflammation and fibrosis driven by the Senescence-Associated Secretory Phenotype (SASP). The human ovary is one of the first organs to age, and prominent age-related fibroinflammation within the ovarian microenvironment is consistent with the presence of senescent cells. However, bona fide senescent cells have not been validated in the human ovary. Therefore, we established a doxorubicin-induced model of cellular senescence to define a signature of ovarian senescent cells. Explants of human postmenopausal ovarian cortex and medulla were treated with doxorubicin for 24 hours followed by culture for up to 10 days in doxorubicin-free medium. Tissue viability was confirmed by histology, lack of apoptosis, and continued glucose consumption by explants. Single nuclei sequencing and proteomics revealed an unbiased signature of ovarian senescence. We identified distinct senescence profiles for the cortex and medulla, driven predominantly by epithelial and stromal cells. Proteomics uncovered subregional differences in addition to 120 proteins common to the cortex and medulla SASP. Integration of transcriptomic and proteomic analyses revealed 26 shared markers, defining a robust senotype of doxorubicin-induced senescence unique to the postmenopausal ovary. A subset of these proteins - Lumican, SOD2, MYH9 , and Periostin - were mapped onto native tissue to reveal compartment-specific localization. This senotype will help determine the role of cellular senescence in ovarian aging and inform the development of biomarkers to identify and therapeutic applications to slow or reverse ovarian aging, senescence, and cancer.
| MSV000095932 | MassIVE
Project description:Introduction Dedifferentiated liposarcoma (DDLPS) is a rare cancer defined by amplification of MDM2 and CDK4. Conventional chemotherapy (Doxorubicin) and targeted inhibition of MDM2 and CDK4 show sporadic responses, but most tumors display primary resistance. We used an unbiased approach to identify therapeutic strategies sensitizing to these DDLPS therapies. Methods Three parallel genome-wide CRISPR-Cas9 knockout screens were conducted in DDLPS cells to sensitize to palbociclib (CDK4 inhibitor), nutlin-3a (MDM2 inhibitor) or Doxorubicin. Top screen hits were validated and characterized in both in vitro and in vivo models, while clinical data were used to corroborate molecular findings. Results We uncovered pathways related to G1/S transition (CDK2, CKS1B, E2F3 and CCNE1) and Non-Homologous End-Joining (NHEJ; TDP2, PRKDC and XRCC4), inactivation of which sensitized to palbociclib and Doxorubicin, respectively. Following validation of both pathways, we focused on mechanistic characterization of Doxorubicin sensitization by genetic perturbation of TDP2 or pharmacological inhibition of DNA-PKcs using peposertib. Synergistic cell cycle arrest and senescence were induced by prolonged administration of low-dose doxorubicin. Senescent cells were triggered to undergo apoptosis by subsequent senolytic treatment with Bcl2 inhibitor navitoclax. Despite the amplification of MDM2, senescence proved dependent on p53. Consistent with this, TCGA and DepMap data suggest p53 activity in DDLPS. Conclusion These findings provide a rationale for targeting the NHEJ pathway to enhance the efficacy of low-dose Doxorubicin in DDLPS, highlighting a potential therapeutic strategy exploiting p53-dependent cell cycle arrest and senescence. Furthermore, we provide, to our knowledge, the first evidence of maintained baseline p53 activity in MDM2-amplified DDLPS.
2026-02-12 | GSE315862 | GEO
Project description:Epithelial senescence, specifically in the bronchiolized regions of the fibrotic lung, is apparent in IPF but not control tissue. In order to better understand the phenotype of these senescent cells we generated a in vitro culture model of senescence utillizing primary normal human bronchial epithelial cells. Cultures were treated with doxorubicin to induce senescence and the transcriptional phenotype of the senescent cultures was compared to DMSO-treated control cultures.
2021-03-08 | GSE166033 | GEO
Project description:Cellular senescence consists of regulated phenotypes associated with permanent exit from the cell cycle in response to stressors such as genomic instability. The consequences of senescence go beyond individual cells due to the senescence associated secretory phenotype (SASP), which can induce inflammation in neighboring cells. Some cancers respond to CDK4/6 inhibitors (CDK4/6i) with a senescence-like phenotype in the absence of extensive DNA damage. We asked how the SASP and the transcriptional regulatory profile triggered by CDK4/6i-driven arrest compares to the canonical NF-κB-regulated SASP triggered by DNA damage. We profiled the dynamics of transcriptional regulation in response to the CDK4/6i, palbociclib, and the DNA damaging agent, doxorubicin. We found upregulation of NF-κB driven-SASP genes was shared across both drugs, although delayed in CDK4/6i, coinciding with slower enhancer activation and epigenetic changes. ATM/ATR inhibition did not affect CDK4/6i-induced NF-κB nuclear localization, suggesting an alternative upstream activator. Inhibiting NF-κB suppressed the expression of SASP genes without reversing stable arrest, pointing to SASP manipulation as a potential therapeutic strategy and providing insights into controversies regarding cell cycle arrest-driven SASP.
2026-06-22 | GSE295258 | GEO
Project description:Cellular senescence consists of regulated phenotypes associated with permanent exit from the cell cycle in response to stressors such as genomic instability. The consequences of senescence go beyond individual cells due to the senescence associated secretory phenotype (SASP), which can induce inflammation in neighboring cells. Some cancers respond to CDK4/6 inhibitors (CDK4/6i) with a senescence-like phenotype in the absence of extensive DNA damage. We asked how the SASP and the transcriptional regulatory profile triggered by CDK4/6i-driven arrest compares to the canonical NF-κB-regulated SASP triggered by DNA damage. We profiled the dynamics of transcriptional regulation in response to the CDK4/6i, palbociclib, and the DNA damaging agent, doxorubicin. We found upregulation of NF-κB driven-SASP genes was shared across both drugs, although delayed in CDK4/6i, coinciding with slower enhancer activation and epigenetic changes. ATM/ATR inhibition did not affect CDK4/6i-induced NF-κB nuclear localization, suggesting an alternative upstream activator. Inhibiting NF-κB suppressed the expression of SASP genes without reversing stable arrest, pointing to SASP manipulation as a potential therapeutic strategy and providing insights into controversies regarding cell cycle arrest-driven SASP.
2026-06-29 | GSE295260 | GEO
Project description:Cellular senescence consists of regulated phenotypes associated with permanent exit from the cell cycle in response to stressors such as genomic instability. The consequences of senescence go beyond individual cells due to the senescence associated secretory phenotype (SASP), which can induce inflammation in neighboring cells. Some cancers respond to CDK4/6 inhibitors (CDK4/6i) with a senescence-like phenotype in the absence of extensive DNA damage. We asked how the SASP and the transcriptional regulatory profile triggered by CDK4/6i-driven arrest compares to the canonical NF-κB-regulated SASP triggered by DNA damage. We profiled the dynamics of transcriptional regulation in response to the CDK4/6i, palbociclib, and the DNA damaging agent, doxorubicin. We found upregulation of NF-κB driven-SASP genes was shared across both drugs, although delayed in CDK4/6i, coinciding with slower enhancer activation and epigenetic changes. ATM/ATR inhibition did not affect CDK4/6i-induced NF-κB nuclear localization, suggesting an alternative upstream activator. Inhibiting NF-κB suppressed the expression of SASP genes without reversing stable arrest, pointing to SASP manipulation as a potential therapeutic strategy and providing insights into controversies regarding cell cycle arrest-driven SASP.
2026-06-22 | GSE295261 | GEO
Project description:Cellular senescence consists of regulated phenotypes associated with permanent exit from the cell cycle in response to stressors such as genomic instability. The consequences of senescence go beyond individual cells due to the senescence associated secretory phenotype (SASP), which can induce inflammation in neighboring cells. Some cancers respond to CDK4/6 inhibitors (CDK4/6i) with a senescence-like phenotype in the absence of extensive DNA damage. We asked how the SASP and the transcriptional regulatory profile triggered by CDK4/6i-driven arrest compares to the canonical NF-κB-regulated SASP triggered by DNA damage. We profiled the dynamics of transcriptional regulation in response to the CDK4/6i, palbociclib, and the DNA damaging agent, doxorubicin. We found upregulation of NF-κB driven-SASP genes was shared across both drugs, although delayed in CDK4/6i, coinciding with slower enhancer activation and epigenetic changes. ATM/ATR inhibition did not affect CDK4/6i-induced NF-κB nuclear localization, suggesting an alternative upstream activator. Inhibiting NF-κB suppressed the expression of SASP genes without reversing stable arrest, pointing to SASP manipulation as a potential therapeutic strategy and providing insights into controversies regarding cell cycle arrest-driven SASP.
2026-06-22 | GSE336040 | GEO
Project description:We established parallel replicative and doxorubicin-induced senescence models in human BJ fibroblasts, demonstrating progressive morphological changes and SA-β-gal activity increases across passages (P3-P33). Molecular analyses confirmed expected senescence markers: p21/p53 upregulation and LMNB1 downregulation at RNA/protein levels. Transcriptomic profiling identified 734 upregulated (extracellular matrix organization) and 195 downregulated (cell cycle) genes. Comparative lncRNA analysis revealed 23 consistently upregulated candidates, with PURPL showing the most dramatic senescence-associated induction. These validated models provide a robust platform for mechanistic aging studies, with PURPL emerging as a key regulator of cellular senescence.
2025-12-02 | GSE301164 | GEO
Project description:Oncogene-induced senescence provides a barrier against malignant transformation. Senescent cells secrete pro-inflammatory cytokines, chemokines and growth factors collectively known as the senescence-associated secretory phenotype (SASP). Paradoxically, the SASP can also negatively impact the neighbouring tissues through inducing an inflammatory environment that promotes tumorigenesis and aged-related pathologies. We have previously shown that the lncRNA MIR31HG is overexpressed and located in the cytoplasm during BRAF-induced senescence. In young proliferating cells, nuclear MIR31HG inhibits p16/CDKN2A expression through interaction with polycomb repressor complexes (PRC1/2). Here, we show that MIR31HG regulates the expression and secretion of a subset of SASP components during BRAF-induced senescence. The SASP secreted from senescent cells depleted for MIR31HG fails to induce paracrine invasion without affecting the growth inhibitory effect. Mechanistically, MIR31HG interacts with the translation factor YBX1 facilitating its phosphorylation at serine 102 (p-YBX1S102) by the kinase RSK. p-YBX1S102 induces IL1A translation which acts as upstream regulator inducing the transcription of the other SASP mRNAs. Our results suggest a dual role for MIR31HG in senescence depending on its cellular localization and place the lncRNA as a potential therapeutic target in the treatment of senescence-related pathologies.
2021-03-02 | PXD017475 | Pride