Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

RNA sequencing analysis of ARV825 target genes in senescent cells

ABSTRACT: Although cellular senescence acts primarily as a tumor suppression mechanism, the accumulation of senescent cells in vivo eventually exerts deleterious side effects through inflammatory/tumor-promoting factor secretion. Thus, the development of new drugs that cause the specific elimination of senescent cells, termed senolysis, is anticipated. Here, by an unbiased high-throughput screening of chemical compounds and a bio-functional analysis, we identify ARV825 as a promising senolytic drug. ARV825 treatment eliminates senescent hepatic stellate cells in obese mouse livers, accompanied by the reduction of liver cancer development. Furthermore, the elimination of chemotherapy-induced senescent cells by ARV825 increases the efficacy of chemotherapy against xenograft tumors in immunocompromised mice. These results reveal the vulnerability of senescent cells and open up possibilities for its control.

ORGANISM(S): Homo sapiens

PROVIDER: GSE140961 | GEO | 2020/03/25

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Chemo-senolytic therapeutic potential against angiosarcoma

Project description:Angiosarcoma is an aggressive soft-tissue sarcoma with a poor prognosis. Chemotherapy for this cancer typically employs paclitaxel, one of the taxanes (genotoxic drugs), although it has a limited effect due to chemoresistance for prolonged treatment. Here we examine a new angiosarcoma treatment approach that combines chemotherapeutic and senolytic agents. We first find that the chemotherapeutic drugs, cisplatin and paclitaxel, efficiently induce cellular senescence of angiosarcoma cells. Subsequent treatment with a senolytic agent, ABT-263, eliminates senescent cells through the activation of the apoptotic pathway. In addition, expression analysis indicates that senescence-associated secretory phenotype (SASP) genes are activated in senescent angiosarcoma cells and that ABT-263 treatment eliminates senescent cells expressing genes in the type-I interferon (IFN-I) pathway. Moreover, we show that cisplatin treatment alone requires a high dose to remove angiosarcoma cells, whereas a lower dose of cisplatin is sufficient to induce senescence, followed by the elimination of senescent cells by senolytic treatment. This study sheds light on a potential therapeutic strategy against angiosarcoma by combining a relatively low dose of cisplatin with the ABT-263 senolytic agent, which can help ease the deleterious side effects of chemotherapy.

2024-03-23 | GSE245935 | GEO

gene expression of aorta of ApoE KO mice after Gpnmb vaccine treatment

Project description:Accumulation of senescent cells in various tissues has been reported to have a pathological role in age-associated diseases. Inhibition of cellular aging signals prevents the onset of age-associated pathology, but there is a risk of promoting carcinogenesis. Elimination of senescent cells (senolysis) was recently reported to reversibly improve pathological changes related to aging in aged mice without increasing the development of cancer. Here we report that glycoprotein nonmetastatic melanoma protein B (Gpnmb) could be a molecular target for senolytic therapy. Elimination of Gpnmb-positive cells by vaccination improved atherosclerosis.

2021-10-22 | GSE155596 | GEO

Photoactivatable senolysis with single-cell resolution reverses aging

Project description:Cellular senescence is a crucial biological process associated with pathologies of aging. The elimination of senescent cells (SnCs) for the purpose to extend healthy lifespan has been supported by emerging evidence, which causes the exploration of drug approaches to induce SnCs death (senolysis). The challenge then becomes how to achieve the precision, broad-spectrum and controllability of senolysis. To this end, we here propose an unprecedented integration strategy to design a senotherapeutic agent

2021-10-27 | GSE186522 | GEO

Single-cell profiling of skeletal muscle reveals a novel senolytic target; CRYAB

Project description:Skeletal muscle mass and function decline with aging, a process known as sarcopenia, and is linked to functional alterations of critical cell types within mature muscle, including fibro-adipogenic progenitors (FAPs) and satellite cells (SCs). Senescence is a form of cellular arrest linked with degenerative diseases of aging, and is thought to be a key driver of aging pathophysiology. We utilized single-cell RNA sequencing to identify novel targets in isolated FAPs and SCs which potentiate senescent cell killing - a process termed senolysis. Using molecular and cellular approaches, we identified the small alpha crystalline heat shock protein CRYAB as a novel senolytic target. We targeted CRYAB using chemical inhibitor screening to identify 25-hydroxycholesterol (25HC), an endogenous metabolite of cholesterol biosynthesis as a potent senolytic capable of killing senescent cells. We validated the potential of 25HC as a senolytic in both mouse and human cells, and in vivo in several tissues including muscle and fat. 25HC treatment therefore represents a potential new class of senolytics, which may be useful in combating diseases or physiologies in which cellular senescence is a key driver.

2022-01-17 | GSE169531 | GEO

Prophilactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction.

Project description:Senescent cells accumulate in organisms over time as a result of tissue damage and impaired immune surveillance and are thought to contribute to age-related tissue decline1,2. In agreement, genetic ablation studies reveal that elimination of senescent cells from aged tissues can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness3-7. While small-molecule drugs capable of eliminating senescent cells (known as ‘senolytics’) partially replicate these phenotypes, many have uncertain mechanisms of action and all require continuous administration to be effective. As an alternative approach, we previously developed a cell-based senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting uPAR, a cell-surface protein upregulated on senescent cells, and showed these can safely and efficiently eliminate senescent cells in young animals and reverse liver fibrosis8. We now show that uPAR-positive senescent cells accumulate during physiological aging and that they can be safely targeted with senolytic CAR T cells in aged animals. Treatment with anti uPAR CAR T cells ameliorates metabolic dysfunction by improving glucose tolerance and exercise capacity in physiological aging as well as in a model of metabolic syndrome. Importantly, the beneficial effects of senolytic CAR T cells are long lasting; single administration of a low dose is sufficient to achieve long-term therapeutic and preventive effects.

2023-12-08 | GSE243616 | GEO

Photoactivatable senolysis with single-cell resolution reverses aging

Project description:Emerging evidence supports the use of pharmaceutical interventions to target senescent cells (SnCs) and induce their death (senolysis) to extend a healthy lifespan. The challenge then becomes how to achieve precise, broad-spectrum and tractable senolysis. To this end, we have designed a novel senotherapeutic agent with an unprecedented integrated strategy

2022-09-24 | GSE213846 | GEO

The YAP-TEAD complex promotes senescent cell survival by lowering endoplasmic reticulum stress [scRNA-seq]

Project description:Sublethal cell damage can trigger a complex adaptive program known as senescence, characterized by growth arrest, resistance to apoptosis, and a senescence-associated secretory phenotype (SASP). As senescent cells accumulating in aging organs are linked to many age-associated diseases, senotherapeutic strategies are actively sought to eliminate them. Here, a whole-genome CRISPR knockout screen revealed that proteins in the YAP-TEAD pathway influenced senescent cell viability. Accordingly, treating senescent cells with a drug that inhibited this pathway, Verteporfin (VPF), selectively triggered apoptotic cell death and derepressed DDIT4, in turn inhibiting mTOR. Reducing mTOR function in senescent cells diminished endoplasmic reticulum (ER) biogenesis, causing ER stress and apoptosis due to high demands on ER function by the SASP. Importantly, VPF treatment decreased senescent cell numbers in the organs of old mice and mice exhibiting doxorubicin-induced senescence. We present a novel senolytic strategy that eliminates senescent cells by hindering ER activity required for SASP production.

2023-07-13 | GSE221117 | GEO

The YAP-TEAD complex promotes senescent cell survival by lowering endoplasmic reticulum stress [bulk RNA-seq]

2023-07-13 | GSE221104 | GEO

The YAP-TEAD complex promotes senescent cell survival by lowering endoplasmic reticulum stress [scRNA-seq_mouse]

2023-07-13 | GSE232273 | GEO

Transcriptome of senescent and non-senescent cells within PanIN pancreatic premalignant lesions in a KRas-driven mouse model

Project description:Cellular senescence is a central barrier to tumorigenesis, acting to block the proliferation of premalignant cells. However, senescent cells residing within tumor lesions can also exert paracrine effects influencing tumor growth and progression. Premalignant pancreatic intraepithelial neoplasia (PanIN) lesions contain senescent cells, yet whether these influence disease progression is unknown. Here we report that senescent cells in PanINs that develop in a Kras-driven mouse model express a pro-inflammatory gene signature, which includes high Cox2 levels. Pharmacologic Cox2 inhibition caused a dramatic reduction in PanIN growth. Senolytic treatment with the Bcl2-family inhibitor ABT-737 reduced the numbers of Cox2-expressing PanIN cells and blocked PanIN formation and progression to carcinoma. These findings indicate that senescent PanIN cells support tumor growth and progression through Cox2 activity, representing crosstalk between interspersed senescent and dividing premalignant cells. Targeted elimination of senescent cells may thus be effective in limiting progression of precancerous lesions.

2021-02-17 | GSE128319 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data