Nintedanib induces senolytic effect via STAT3 inhibition
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA863375 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR20701700_1.fastq.gz | Fastqsanger.gz | |||
| SRR20701700_2.fastq.gz | Fastqsanger.gz | |||
| SRR20701701_1.fastq.gz | Fastqsanger.gz | |||
| SRR20701701_2.fastq.gz | Fastqsanger.gz | |||
| SRR20701702_1.fastq.gz | Fastqsanger.gz |
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Project description:Selective removal of senescent cells, or the concept of senolytic therapy, has been proposed to be a potent strategy for overcoming age-related diseases and even reversing aging. We found that nintedanib, a tyrosine kinase inhibitor, selectively induced cell death in primary human diploid fibroblasts undergoing replicative senescence. Similar to ABT263, a well-known senolytic agent, nintedanib triggered intrinsic apoptosis in senescent cells. Additionally, at the concentration producing the senolytic effect, nintedanib arrested the cell cycle of nonsenescent cells in the G1 phase without cytotoxicity. Interestingly, compared with ABT263, nintedanib showed a different mode of activating caspase-9 in the intrinsic apoptotic pathway, in that nintedanib did not suppress the levels of Bcl-2 family proteins in senescent cells. In more detail, nintedanib suppressed the activation of the JAK2/STAT3 pathway, which caused drug-induced cell death in senescent cells. STAT3 knockdown in senescent cells also induced caspase activation. Moreover, nintedanib reduced the number of senescent cells stained based on senescence-associated β-galactosidase activity and airway resistance in a mouse model of bleomycin-induced lung fibrosis. Overall, we identified that nintedanib could be used as a new senolytic agent and that inhibiting STAT3 could be a potential approach for inducing selective cell death in senescent cells. Our findings will pave the way for expanding senolytic toolkits in response to various aging statuses and age-related diseases.
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Project description:Nintedanib is a potent anti-fibrotic angio-kinase inhibitor, which has shown clinical efficacy in combination with chemotherapy in locally advanced muscle invasive BC patients. Nintedanib inhibits Fibroblast Growth Factor receptors (FGFRs), validated targets in patients with BC harboring FGFR3/2 genetic alterations. Here, we aimed at studying its mechanisms of action to understand therapy their combination (n=4). Reads were mapped separately against the human and mouse genomes to differentiate tumor vs. stromal expression changes
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Project description:Nintedanib is a potent anti-fibrotic angio-kinase inhibitor, which has shown clinical efficacy in combination with chemotherapy in locally advanced muscle invasive BC patients. Nintedanib inhibits Fibroblast Growth Factor receptors (FGFRs), validated targets in patients with BC harboring FGFR3/2 genetic alterations. Here, we aimed at studying its mechanisms of action to understand therapy their combination (n=4). Reads were mapped separately against the human and mouse genomes to differentiate tumor vs. stromal expression changes
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Project description:Activation of Signal Transducer and Activator of Transcription 3 (STAT3) is common in prostate cancers. STAT3 may induce cell proliferation and resistance to apoptosis, as well as promote tumor angiogenesis, invasion, and migration by activating gene expression. Many STAT3-dependent transcriptional responses are mediated through protein-protein interactions that involve the amino-terminal domain (N-domain). In this study, we found that inhibition of the STAT3 N-domain using novel inhibitor ST3-Hel2A-2 induces apoptotic death in prostate cancer cells. The cell death was accomponied by robust activation of pro-apoptotic gene. Using chromatin immunoprecipitation and tiling human promoter arrays (ChIP-chip), we have defined genome-wide targets of STAT3 in DU145 prostate cancer cells. We found that upregulated pro-apoptotic genes were bound by STAT3 in prostate cancer cells, and that STAT3 binding was decreased following inhibition of the STAT3 N-domain. STAT3 siRNA knockdow confirmed specificity of STAT3 binding and changes in gene expression. DU145 cells were treated with STAT3 siRNA or scrambled siRNA for 48hr. Total RNA has been extracted and prepared for hybridization on Affymetrix HG-U133A 2.0 arrays.
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Project description:Activation of Signal Transducer and Activator of Transcription 3 (STAT3) is common in prostate cancers. STAT3 may induce cell proliferation and resistance to apoptosis, as well as promote tumor angiogenesis, invasion, and migration by activating gene expression. Many STAT3-dependent transcriptional responses are mediated through protein-protein interactions that involve the amino-terminal domain (N-domain). In this study, we found that inhibition of the STAT3 N-domain using novel inhibitor ST3-Hel2A-2 induces apoptotic death in prostate cancer cells. The cell death was accomponied by robust activation of pro-apoptotic gene. Using chromatin immunoprecipitation and tiling human promoter arrays (ChIP-chip), we have defined genome-wide targets of STAT3 in DU145 prostate cancer cells. We found that upregulated pro-apoptotic genes were bound by STAT3 in prostate cancer cells, and that STAT3 binding was decreased following inhibition of the STAT3 N-domain. DU145 cells were treated with ST3-Hel2A-2 or DMSO as a control for 3 hr. Total RNA has been extracted and prepared for hybridization on Affymetrix HG-U133A 2.0 arrays.
2010-12-07 | E-GEOD-25866 | biostudies-arrayexpress
Project description:Transcriptomic analysis of Nintedanib, Alpelisib and Nintedanib Alpelisib treated bladder tumors
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Project description:Ovarian carcinoma (OC) is the fifth leading cause of death among women in the United States. Persistent activation of signal transducer and activator of transcription (STAT3) is frequently detected in OC. STAT3 is activated by Janus family kinases (JAK) via cytokine receptors, growth factor receptor and non-growth factor receptor tyrosine kinases. Activation of STAT3 mediates tumor cell proliferation, survival, motility, invasion, and angiogenesis, and recent work demonstrates that STAT3 activation suppresses anti-tumor immune responses and supports tumor-promoting inflammation. We hypothesized that therapeutic targeting of the JAK/STAT3 pathway would inhibit tumor growth by direct effects on OC cells and by inhibition of cells in the tumor microenvironment (TME). To test this, we evaluated the effects of a small molecule JAK inhibitor, AZD1480, on cell viability, apoptosis, proliferation, migration and adhesion of OC cells in vitro. We then evaluated the effects of AZD1480 on in vivo tumor growth and progression, gene expression, tumor-associated matrix metalloproteinase (MMP) activity and immune cell populations in a transgenic mouse model of OC. AZD1480-treatment inhibited STAT3 phosphorylation and DNA binding, and migration and adhesion of cultured OC cells and ovarian tumor growth rate, volume and ascites production in mice. In addition, drug treatment led to altered gene expression, decreased tumor-associated MMP activity, and fewer suppressor T cells in the peritoneal tumor microenvironment of tumor-bearing mice than control mice. Taken together, our results show pharmacological inhibition of the JAK2/STAT3 pathway leads to disruption of functions essential for ovarian tumor growth and progression and represents a promising therapeutic strategy. 8 female C57BL/6JTgMISIIR-TAg mice with ovarian tumors of ~500 mm3 were used. 4 vehicle-treated mice (0.5% hypermellose/0.1%Tween 80);4 drug-treated mice (30 mg/kg AZD1480 in 0.5% hypermellose/0.1%Tween 80).
2015-02-01 | E-GEOD-63092 | biostudies-arrayexpress
Project description:Idiopathic pulmonary fibrosis (IPF) is a progressing chronic and fibrotic lung response with poor prognosis. The current standard-of-care for IPF is the kinase inhibitor nintedanib, which has a broad target range. The mechanism of nintedanib’s action remains unclear as it inhibits diverse kinases expressed in lung epithelia, endothelia and putatively the immune populations distributed throughout the lung. Given the proposed role of multiple pulmonary macrophage populations in mediating both protective and pathogenic roles in lung fibrosis, we sought to identify repair-associated macrophage populations in mice influenced by nintedanib after bleomycin challenge for 7 and 14 days using single cell RNA sequencing. Bleomycin exposure triggered expansion of inflammatory MHCIIhigh macrophage populations, which was partially reversed after nintedanib treatment. Concurrently, nintedanib promoted the expansion of MHCIIlow macrophages, which were linked to attenuation of lung fibrosis. Concomitantly, nintedanib promoted an increased expression of mRNA for canonical macrophage repair markers in MHCIIlow macrophages. Finally, exposure of inflammatory macrophages to nintedanib in vitro resulted in attenuation of expression of transcripts for MCHII. In conclusion, a component of nintedanib’s protective mode of action in lung fibrosis relies on expanding distinct MHCIIlow macrophage populations and redirecting them toward a reparative phenotype. This study provides a rationale for further refinement of therapeutic kinase inhibition in fibrotic diseases.
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Project description:Advances in the clinical management of pediatric B cell Acute Lymphoblastic Leukemia (B-ALL) have dramatically improved outcomes for this disease. However, relapsed and high-risk disease still contribute to significant numbers of treatment failures. Development of new, broad range therapies is urgently needed for these cases. We previously reported the susceptibility of ETV6-RUNX1+ pediatric B-ALL to inhibition of signal transducer and activator of transcription 3 (STAT3) activity. In the present study, we demonstrate that pharmacological or genetic inhibition of STAT3 results in p53 induction and that CRISPR-mediated TP53 knockout substantially reverses susceptibility to STAT3 inhibition. Furthermore, we demonstrate that sensitivity to STAT3 inhibition in patient-derived xenograft (PDX) B-ALL samples is not restricted to any particular disease subtype, but rather depends on TP53 status, the only resistant samples being TP53 mutant. Induction of p53 following STAT3 inhibition is MDM2-independent and exhibits synergistic in vitro and in vivo anti leukemia activity when combined with MDM2 inhibition. Taken together with the relatively low frequency of TP53 mutations in this disease, these data support the future development of combined STAT3/MDM2 inhibition in the therapy of refractory and relapsed pediatric B-ALL.
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