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Ponatinib-induced cardiotoxicity is driven by S100A8/A9-NLRP3-IL-1β signaling mediated excessive inflammation

ABSTRACT: Ponatinib-induced cardiotoxicity is driven by S100A8/A9-NLRP3-IL-1β signaling mediated excessive inflammation

PROVIDER: PRJNA908827 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22533662_1.fastq.gz	Fastqsanger.gz
	SRR22533662_2.fastq.gz	Fastqsanger.gz
	SRR22533663_1.fastq.gz	Fastqsanger.gz
	SRR22533663_2.fastq.gz	Fastqsanger.gz
	SRR22533664_1.fastq.gz	Fastqsanger.gz

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Ponatinib-induced cardiotoxicity is driven by S100A8/A9-NLRP3-IL-1β signaling mediated excessive inflammation

Project description:To delineate the underlying molecular mechanisms of ponatinib-induced cardiotoxicity, we used we a comorbitity cardiotoxicity mouse model (high fat-fed ApoE-/- mice) treated for two weeks with placebo/ or Ponatinib We then performed gene expression profiling analysis on left ventricular tissues from the two mouse groups

2023-02-08 | GSE220121 | GEO

S100A8/A9 activate key genes and pathways in colon tumor progression

Project description:Studies using bone marrow chimeric mice revealed that S100A8/A9 expression on myeloid cells is essential for development of colon tumors. Our results thus reveal a novel role for myeloid-derived S100A8/A9 in activating specific downstream genes associated with tumorigenesis and in promoting tumor growth and metastasis. Subconfluent cultures of MC38 cells were serum-starved for 16 hrs and activated with 10ug/mL S100A8/A9 for 6 hrs. Total RNA was extracted from unactivated or activated cells. 2 replicates each per stimulated cells, unstimulated cells, and control cells.

2011-02-01 | E-GEOD-26359 | biostudies-arrayexpress

S100A8/A9 activate key genes and pathways in colon tumor progression

2011-02-01 | GSE26359 | GEO

S100A8/A9 induced by interaction with macrophages in esophageal squamous cell carcinoma promotes the migration and invasion of cancer cells via Akt and p38 MAPK pathways

Project description:Tumor-associated macrophages enhance the malignant phenotypes of esophageal squamous cell carcinoma (ESCC) cells. We have previously identified several factors associated with ESCC progression using an indirect co-culture assay between ESCC cells and macrophages. Here, we newly established a direct co-culture assay between ESCC cells and macrophages which is closer to the actual cancer microenvironment than an indirect co-culture assay. To investigate the gene expression changes by co-culture with macrophages, we performed cDNA microarray analysis between mono-cultured and co-cultured ESCC cells with macrophages. We found that the expression of S100 calcium binding protein A8 and A9 (S100A8 and S100A9) was enhanced in co-cultured ESCC cells with macrophages. S100A8 and S100A9 commonly exist stable and function as a heterodimer (S100A8/A9). S100A8/A9 is widely known as an inflammation marker. It also contributes to the enhancement of malignant phenotypes in several cancers. S100A8/A9 enhances the migration and invasion of ESCC cells by activating Akt and p38 MAPK signaling pathways. The higher expression levels of S100A8/A9 were associated with poor prognosis in ESCC patients. These results suggest that S100A8/A9 contributes to the progression of ESCC.

2021-12-01 | GSE174796 | GEO

Ponatinib Drives Cardiotoxicity by S100A8/A9-NLRP3-IL-1β Mediated Inflammation.

Project description:BackgroundThe tyrosine kinase inhibitor ponatinib is the only treatment option for chronic myelogenous leukemia patients with T315I (gatekeeper) mutation. Pharmacovigilance analysis of Food and Drug Administration and World Health Organization datasets has revealed that ponatinib is the most cardiotoxic agent among all Food and Drug Administration-approved tyrosine kinase inhibitors in a real-world scenario. However, the mechanism of ponatinib-induced cardiotoxicity is unknown.MethodsThe lack of well-optimized mouse models has hampered the in vivo cardio-oncology studies. Here, we show that cardiovascular comorbidity mouse models evidence a robust cardiac pathological phenotype upon ponatinib treatment. A combination of multiple in vitro and in vivo models was employed to delineate the underlying molecular mechanisms.ResultsAn unbiased RNA sequencing analysis identified the enrichment of dysregulated inflammatory genes, including a multifold upregulation of alarmins S100A8/A9, as a top hit in ponatinib-treated hearts. Mechanistically, we demonstrate that ponatinib activates the S100A8/A9-TLR4 (Toll-like receptor 4)-NLRP3 (NLR family pyrin domain-containing 3)-IL (interleukin)-1β signaling pathway in cardiac and systemic myeloid cells, in vitro and in vivo, thereby leading to excessive myocardial and systemic inflammation. Excessive inflammation was central to the cardiac pathology because interventions with broad-spectrum immunosuppressive glucocorticoid dexamethasone or specific inhibitors of NLRP3 (CY-09) or S100A9 (paquinimod) nearly abolished the ponatinib-induced cardiac dysfunction.ConclusionsTaken together, these findings uncover a novel mechanism of ponatinib-induced cardiac inflammation leading to cardiac dysfunction. From a translational perspective, our results provide critical preclinical data and rationale for a clinical investigation into immunosuppressive interventions for managing ponatinib-induced cardiotoxicity.

| S-EPMC9898181 | biostudies-literature

Hematopoietic progenitor cell liabilities and alarmins S100A8/A9 – related inflammaging associate with frailty and predict poor cardiovascular outcomes in older adults

Project description:Frailty affects the physical, cognitive, and social domains exposing older adults to an increased risk of cardiovascular disease (CVD) and death. The mechanisms linking frailty and cardiovascular outcomes are mostly unknown. Here, we studied the association of abundance (flow cytometry) and gene expression profile (RNAseq) of stem/progenitor cells (HSPCs) and molecular markers of inflammaging (ELISA) with the cardiorespiratory phenotype and prospective adverse events of individuals classified according to levels of frailty. Two cohorts of older adults were enrolled in the study. In a cohort of pre-frail 35 individuals (average age: 75 years), a physical frailty score above the median identified subjects with initial alterations in cardiorespiratory function. RNA sequencing revealed S100A8/A9 upregulation in HSPCs from the bone marrow (>10-fold) and peripheral blood (>200-fold) of individuals with greater physical frailty. Moreover higher frailty was associated with increased alarmins S100A8/A9 and inflammatory cytokines in peripheral blood. We then studied a cohort of 104 more frail individuals (average age: 81 years) with multi-domain health deficits. Reduced levels of circulating HSPCs and increased S100A8/A9 concentrations were independently associated with the frailty index. Remarkably, low HSPCs and high S100A8/A9 simultaneously predicted major adverse cardiovascular events at 1-year follow-up after adjustment for age and frailty index. In conclusion, inflammaging characterized by alarmin and pro-inflammatory cytokines in pre-frail individuals is mirrored by the pauperization of HSPCs in frail older people with comorbidities. S100A8/A9 is upregulated within HSPCs, identifying a phenotype that associates with poor cardiovascular outcomes.

2022-03-23 | GSE190446 | GEO

E-selectin-mediated rapid NLRP3 inflammasome activation regulates S100A8/A9 release from neutrophils via transient gasdermin D pore formation

Project description:S100A8/A9 is a proinflammatory mediator released by myeloid cells during many acute and chronic inflammatory disorders. However, the precise mechanism of its release from the cytosolic compartment of neutrophils is still elusive. We report here that E-selectin-induced rapid S100A8/A9 release during inflammation occurs in a NLRP3 inflammasome-dependent fashion. Mechanistically, E-selectin engagement triggers Bruton?s tyrosine kinase dependent tyrosine phosphorylation of NLRP3. Concomitant potassium efflux via the voltage-gated potassium channel KV1.3 mediates ASC oligomerization. This is followed by caspase-1 cleavage and downstream activation of pore forming gasdermin D, enabling cytosolic S100A8/A9 to be released. Strikingly, E-selectin-mediated gasdermin D pore formation does not result in cell death, but is a transient process involving activation of the ESCRT-III membrane repair machinery. These findings do not only elucidate the molecular mechanisms of controlled S100A8/A9 release but also identify the NLRP3/gasdermin D axis as a rapid and reversible activation system in neutrophils during inflammation.

2023-10-25 | PXD041652 | Pride

S100A8/S100A9 cytokine functions as transcriptional coactivator during breast cellular transformation

Project description:In an inducible model of human breast cellular transformation, we map genome-wide chromatin binding of S100A8, S100A9 and Pol II. We show that the calcium-dependent cytokines S100A8 and S100A9 are recruited to numerous promoters and enhancers. This recruitment is associated with multiple DNA sequence motifs recognized by DNA-binding transcription factors that are linked to transcriptional activation and are important for transformation. Nuclear-specific expression of S100A8/A9 promotes oncogenic transcription and leads to enhanced breast transformation phenotype. These results suggest that, in addition to its classical cytokine function, S100A8/A9 can act as a transcriptional co-activator.

2021-01-01 | GSE155421 | GEO

A proteome-wide screen identifies the calcium binding proteins, S100A8/S100A9, as clinically relevant therapeutic targets in aortic dissection: a translational study [scRNA-seq]

Project description:S100A8 and S100A9 (aliases MRP8 and MRP14) are highly expressed in neutrophils and monocytes and are classified as damage-associated molecular pattern (DAMP) molecules or alarm molecules. However, the role of S100A8/A9 in aortic dissection has not been reported. In the present study, by employing an unbiased proteomics approach and RNA sequencing analysis , we found that the protein expression of calcium binding proteins S100A8/A9 were upregulated in the aorta and serum of TAAAD patients and also in a mouse model.

2024-05-06 | GSE247260 | GEO

Highly efficient and multiplexed transcriptome profiling of cardiotoxicity induced by tyrosine kinase inhibitors

Project description:Tyrosine kinase inhibitors (TKIs) are anti-cancer therapeutics used in long-term treatment. However, many of them cause cardiotoxicity with limited cure. We aim to define molecular mechanisms of cardiotoxicity that can be targeted for oncocardiology treatment. Eight TKIs with different levels of cardiotoxicity were selected and transcriptome responses of human cardiomyocytes to them at varying doses and times were profiled using a high throughput RNAseq technique. Transcriptome changes are classified into 7 clusters with mainly single-drug clusters. Drug-specific effects on the transcriptome dominate over dose-, time- or toxicity-dependent effects. Two clusters with three TKIs (afatinib, ponatinib and sorafenib) have the top enriched pathway as the endoplasmic reticulum stress. These TKIs cause an increase in reactive oxygen species, lipid peroxidation, or calcium, and induce biased endoplasmic reticulum stress on the PERK and the IRE1α pathway. Inhibiting either PERK or IRE1α blocks expression of cardiomyocyte injury and pro-inflammatory markers. Our data contain rich information about stress responses of human cardiomyocytes to specific TKIs, representing potential molecular mechanisms of cardiotoxicity. ER stress-induced inflammation is a promising therapeutic target to mitigate ponatinib- and sorafenib-induced cardiotoxicity

2023-05-12 | GSE221595 | GEO

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