Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA276172 | ENA |
REPOSITORIES: ENA
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Project description:Senescent cells drive ageing and age-related pathologies, including cancer. Consequently, senolytics, drugs that selectively kill senescent cells, have a broad therapeutic appeal. Here, we report a senolytic screen of a library of 10,480 covalent fragments. Amongst 38 identified hits, we found a subset of chloroacetamides with broad senolytic activity. Activity-based protein profiling, coupled with functional assays, identified the glutathione peroxidase GPX4 as their target. We show that senescent cells are primed for ferroptosis, displaying high levels of oxidative stress, intracellular Fe2+, and enhanced lipid oxidation, but also upregulate GPX4, which protects them from ferroptosis. Consequently, treatment with senolytic chloroacetamides or GPX4 inhibitors selectively kills senescent cells by ferroptosis. The combination of anti-cancer therapies with GPX4 inhibitors eliminated senescent tumour cells and improved outcomes in models of prostate and ovarian cancer. Our results show that senescent cells rely on GPX4 to prevent ferroptosis and that GPX4 inhibitors kill senescent cells, having a wide therapeutic potential.
2026-02-23 | PXD068417 | Pride
Project description:Senescent cells drive ageing and age-related pathologies, including cancer. Consequently, senolytics, drugs that selectively kill senescent cells, have a broad therapeutic appeal. Here, we report a senolytic screen of a library of 10,480 covalent fragments. Amongst 44 identified hits, we found a subset of chloroacetamides with broad senolytic activity. Activity-based protein profiling, coupled with functional assays, identified the glutathione peroxidase GPX4 as their target. Senescent cells are primed for ferroptosis, displaying high levels of oxidative stress, intracellular Fe2+, and enhanced lipid oxidation, but also display increased levels of GPX4, which protects them from ferroptosis. Consequently, treatment with senolytic chloroacetamides or GPX4 inhibitors selectively kills senescent cells by ferroptosis. The combination of anti-cancer therapies with GPX4 inhibitors eliminated senescent tumour cells and improved outcomes in models of prostate and ovarian cancer. Our results show that senescent cells rely on GPX4 to prevent ferroptosis and that GPX4 inhibitors kill senescent cells, having a wide therapeutic potential.
2026-02-23 | PXD068572 | Pride
Project description:In the treatment of cancer with chemotherapeutics, it has been observed that a significant amount of cancer cells turn into senescent cells. These senescent cells secrete several factors in their microenvironment called SASP. Therefore, recently, to develop the senolytic and/or senomorphic drugs, targeting the senescent cells gains importance as a new strategy for preventing the damage that senescent cancer cells cause. In the current work, we evaluated whether Rho/Rho kinase pathway has a potential to be used as a target pathway for the development of senolytic and/or senomorphic drugs, in doxorubicin-induced senescent cancer cell lines. We performed a whole-genome microarray analysis to determine how the expressions of SASP factors change in senescent cells and whether ROCK inhibition also causes changes in the expression of these factors.
2021-04-13 | GSE160234 | GEO
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
Project description:Cellular senescence contributes to a variety of pathologies associated with aging and is implicated as a cellular state in which cancer cells can survive treatment. Reported senolytic drug treatments act through varying molecular mechanisms, but heterogeneous efficacy across the diverse contexts of cellular senescence indicates a need for predictive biomarkers of senolytic activity. Using multi-parametric analyses of commonly reported molecular features of the senescent phenotype, we assayed a variety of models, including malignant and nonmalignant cells, using several triggers of senescence induction and found no predictive power of these traditional senescence markers to identify senolytic drug sensitivity. We sought to identify novel drug targets in senescent cells that were insensitive to frequently implemented senolytic therapies, such as Navitoclax (ABT263), using quantitative mass spectrometry to measure changes in the senescent proteome, compared to cells which acquire an acute sensitivity to ABT263 with senescence induction. Inhibition of the antioxidant GPX4 or the Bcl-2 family member MCL-1 using small molecule compounds in combination with ABT263 significantly increased the induction of apoptosis in some, but not all, previously insensitive senescent cells. We then asked if we could use BH3 profiling to measure differences in mitochondrial apoptotic priming in these models of cellular senescence and predict sensitivity to the ABT263 or the combination of dasatinib and quercetin (D+Q). We found, despite being significantly less primed for apoptosis overall, the dependence of senescent mitochondria on BCL-xL was significantly correlated to senescent cell killing by both ABT263 and D+Q, despite no significant changes in the gene or protein expression of BCL-xL. However, our data caution against broad classification of drugs as globally senolytic and instead provide impetus for context-specific senolytic targets and propose BH3 profiling as an effective predictive biomarker.
2024-12-17 | PXD054626 | Pride
Project description:Gene expression profiling of immortalized human mesenchymal stem cells with hTERT/E6/E7 transfected MSCs. hTERT may change gene expression in MSCs. Goal was to determine the gene expressions of immortalized MSCs.
2010-09-25 | GSE24338 | GEO
Project description:Kynureninase is a member of a large family of catalytically diverse but structurally homologous pyridoxal 5'-phosphate (PLP) dependent enzymes known as the aspartate aminotransferase superfamily or alpha-family. The Homo sapiens and other eukaryotic constitutive kynureninases preferentially catalyze the hydrolytic cleavage of 3-hydroxy-l-kynurenine to produce 3-hydroxyanthranilate and l-alanine, while l-kynurenine is the substrate of many prokaryotic inducible kynureninases. The human enzyme was cloned with an N-terminal hexahistidine tag, expressed, and purified from a bacterial expression system using Ni metal ion affinity chromatography. Kinetic characterization of the recombinant enzyme reveals classic Michaelis-Menten behavior, with a Km of 28.3 +/- 1.9 microM and a specific activity of 1.75 micromol min-1 mg-1 for 3-hydroxy-dl-kynurenine. Crystals of recombinant kynureninase that diffracted to 2.0 A were obtained, and the atomic structure of the PLP-bound holoenzyme was determined by molecular replacement using the Pseudomonas fluorescens kynureninase structure (PDB entry 1qz9) as the phasing model. A structural superposition with the P. fluorescens kynureninase revealed that these two structures resemble the "open" and "closed" conformations of aspartate aminotransferase. The comparison illustrates the dynamic nature of these proteins' small domains and reveals a role for Arg-434 similar to its role in other AAT alpha-family members. Docking of 3-hydroxy-l-kynurenine into the human kynureninase active site suggests that Asn-333 and His-102 are involved in substrate binding and molecular discrimination between inducible and constitutive kynureninase substrates.
| S-EPMC2531291 | biostudies-literature
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
Project description:RNA extracted at 240min. Samples are rRNA depleted. Expression measurement of Homo sapiens genes.
2019-07-31 | GSE114179 | GEO
Project description:Senolytics, drugs that kill senescent cells, have been proposed to improve the response to pro-senescence cancer therapies. However, lack of broadly acting senolytic drugs remains a challenge. Using inducible CRISPR/Cas9-based genetic screens in different senescent cancer cell models, we identify here loss of the death receptor inhibitor cFLIP as a universal vulnerability of senescent cancer cells. Senescent cancer cells are primed for apoptotic death by NF-kB-mediated upregulation of death receptor DR5 and its ligand TRAIL but are protected from death by increased cFLIP. Activation of DR5 signaling by agonistic antibody, which can be enhanced further by suppression of cFLIP by BRD2 inhibition, leads to efficient killing of all senescent cancer cells tested. We validate this ?one-two punch? cancer therapy by combining pro-senescence therapy with DR5 activation in different animal models.
2022-08-24 | GSE191255 | GEO