Browse
Submit Data
Databases
API
Help

Dataset Information

21 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Modulation of therapy-induced senescence by reactive lipid aldehydes.

ABSTRACT: Current understanding points to unrepairable chromosomal damage as the critical determinant of accelerated senescence in cancer cells treated with radiation or chemotherapy. Nonetheless, the potent senescence inducer etoposide not only targets topoisomerase II to induce DNA damage but also produces abundant free radicals, increasing cellular reactive oxygen species (ROS). Toward examining roles for DNA damage and oxidative stress in therapy-induced senescence, we developed a quantitative flow cytometric senescence assay and screened 36 redox-active agents as enhancers of an otherwise ineffective dose of radiation. While senescence failed to correlate with total ROS, the radiation enhancers, etoposide and the other effective topoisomerase inhibitors each produced high levels of lipid peroxidation. The reactive aldehyde 4-hydroxy-2-nonenal, a lipid peroxidation end product, was sufficient to induce senescence in irradiated cells. In turn, sequestering aldehydes with hydralazine blocked effects of etoposide and other senescence inducers. These results suggest that lipid peroxidation potentiates DNA damage from radiation and chemotherapy to drive therapy-induced senescence.

SUBMITTER: Flor AC

PROVIDER: S-EPMC4957821 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

A signature of enhanced lipid metabolism, lipid peroxidation and aldehyde stress in therapy-induced senescence.

Project description:At their proliferative limit, normal cells arrest and undergo replicative senescence, displaying large cell size, flat morphology, and senescence-associated beta-galactosidase (SA-β-Gal) activity. Normal or tumor cells exposed to genotoxic stress undergo therapy-induced senescence (TIS), displaying a similar phenotype. Senescence is considered a DNA damage response, but cellular heterogeneity has frustrated identification of senescence-specific markers and targets. To explore the senescent cell proteome, we treated tumor cells with etoposide and enriched SA-β-GalHI cells by fluorescence-activated cell sorting (FACS). The enriched TIS cells were compared to proliferating or quiescent cells by label-free quantitative LC-MS/MS proteomics and systems analysis, revealing activation of multiple lipid metabolism pathways. Senescent cells accumulated lipid droplets and imported lipid tracers, while treating proliferating cells with specific lipids induced senescence. Senescent cells also displayed increased lipid aldehydes and upregulation of aldehyde detoxifying enzymes. These results place deregulation of lipid metabolism alongside genotoxic stress as factors regulating cellular senescence.

| S-EPMC5661608 | biostudies-literature

Mass spectrometry dataset on apo-SOD1 modifications induced by lipid aldehydes.

Project description:Metal-deficient Cu,Zn-superoxide dismutase (apo-SOD1) is associated with the formation of SOD1 aggregates that accumulate in ALS disease. The data supplied in this article support the accompanying publication showing SOD1 modification and aggregation induced by lipid aldehydes [1]. Here, we present the LC-MS/MS dataset on apo-SOD1 modification induced by seven different lipid aldehydes: 4-hydroxy-2-hexenal (HHE), 4-hydroxy-2-nonenal (HNE), 2-hexen-1-al (HEX), 2,4-nonadienal (NON), 2,4-decadienal (DEC) or secosterol aldehydes (SECO-A or SECO-B). Modified protein samples were digested with trypsin and sequenced by a LC coupled to a Q-TOF instrument. Protein sequencing and peptide modification analysis was performed by Mascot 2.6 (Matrix Science) and further validated by manual inspection. Mass spectrometry data (RAW files) obtained in this study have been deposited to MassIVE and the observed peptide-aldehyde adducts can be used in further studies exploring SOD1 modifications in vivo.

| S-EPMC7316990 | biostudies-literature

Therapy-Induced Senescence: Opportunities to Improve Anticancer Therapy.

Project description:Cellular senescence is an essential tumor suppressive mechanism that prevents the propagation of oncogenically activated, genetically unstable, and/or damaged cells. Induction of tumor cell senescence is also one of the underlying mechanisms by which cancer therapies exert antitumor activity. However, an increasing body of evidence from preclinical studies demonstrates that radiation and chemotherapy cause accumulation of senescent cells (SnCs) both in tumor and normal tissue. SnCs in tumors can, paradoxically, promote tumor relapse, metastasis, and resistance to therapy, in part, through expression of the senescence-associated secretory phenotype. In addition, SnCs in normal tissue can contribute to certain radiation- and chemotherapy-induced side effects. Because of its multiple roles, cellular senescence could serve as an important target in the fight against cancer. This commentary provides a summary of the discussion at the National Cancer Institute Workshop on Radiation, Senescence, and Cancer (August 10-11, 2020, National Cancer Institute, Bethesda, MD) regarding the current status of senescence research, heterogeneity of therapy-induced senescence, current status of senotherapeutics and molecular biomarkers, a concept of "one-two punch" cancer therapy (consisting of therapeutics to induce tumor cell senescence followed by selective clearance of SnCs), and its integration with personalized adaptive tumor therapy. It also identifies key knowledge gaps and outlines future directions in this emerging field to improve treatment outcomes for cancer patients.

| S-EPMC8486333 | biostudies-literature

Therapy-Induced Senescence Drives Bone Loss.

Project description:Chemotherapy is important for cancer treatment, however, toxicities limit its use. While great strides have been made to ameliorate the acute toxicities induced by chemotherapy, long-term comorbidities including bone loss remain a significant problem. Chemotherapy-driven estrogen loss is postulated to drive bone loss, but significant data suggests the existence of an estrogen-independent mechanism of bone loss. Using clinically relevant mouse models, we showed that senescence and its senescence-associated secretory phenotype (SASP) contribute to chemotherapy-induced bone loss that can be rescued by depleting senescent cells. Chemotherapy-induced SASP could be limited by targeting the p38MAPK-MK2 pathway, which resulted in preservation of bone integrity in chemotherapy-treated mice. These results transform our understanding of chemotherapy-induced bone loss by identifying senescent cells as major drivers of bone loss and the p38MAPK-MK2 axis as a putative therapeutic target that can preserve bone and improve a cancer survivor's quality of life. SIGNIFICANCE: Senescence drives chemotherapy-induced bone loss that is rescued by p38MAPK or MK2 inhibitors. These findings may lead to treatments for therapy-induced bone loss, significantly increasing quality of life for cancer survivors.

| S-EPMC7056549 | biostudies-literature

Hepatocellular Senescence: Immunosurveillance and Future Senescence-Induced Therapy in Hepatocellular Carcinoma.

Project description:Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. The lack of effective targeted drugs has become a challenge on treating HCC patients. Cellular senescence is closely linked to the occurrence, development, and therapy of tumor. Induction of cellular senescence and further activation of immune surveillance provides a new strategy to develop HCC targeted drugs, that is, senescence-induced therapy for HCC. Precancerous hepatocytes or HCC cells can be induced into senescent cells, subsequently producing senescence-associated secretory phenotype (SASP) factors. SASP factors recruit and activate various types of immune cells, including T cells, NK cells, macrophages, and their subtypes, which carry out the role of immune surveillance and elimination of senescent cells, ultimately preventing the occurrence of HCC or inhibiting the progression of HCC. Specific interventions in several checkpoints of senescence-mediated therapy will make positive contributions to suppress tumorigenesis and progression of HCC, for instance, by applying small molecular compounds to induce cellular senescence or selecting cytokines/chemokines to activate immunosurveillance, supplementing adoptive immunocytes to remove senescent cells, and screening chemical drugs to induce apoptosis of senescent cells or accelerate clearance of senescent cells. These interventional checkpoints become potential chemotherapeutic targets in senescence-induced therapy for HCC. In this review, we focus on the frontiers of senescence-induced therapy and discuss senescent characteristics of hepatocytes during hepatocarcinogenesis as well as the roles and mechanisms of senescent cell induction and clearance, and cellular senescence-related immunosurveillance during the formation and progression of HCC.

| S-EPMC7732623 | biostudies-literature

Mcl-1 regulates reactive oxygen species via NOX4 during chemotherapy-induced senescence.

Project description:Mcl-1, a Bcl-2 family member, is highly expressed in a variety of human cancers and is believed to enhance tumorigenic potential and chemotherapy resistance through the inhibition of apoptosis and senescence. We previously reported that Mcl-1's regulation of chemotherapy-induced senescence (CIS) is dependent on its ability to prevent reactive oxygen species (ROS) generation. In this report, we demonstrate that Mcl-1-regulated CIS requires not only ROS, but specifically mitochondrial ROS, and that these events are upstream of activation of the DNA damage response, another necessary step toward senescence. Mcl-1's anti-senescence activity also involves the unique ability to inhibit ROS formation by preventing the upregulation of pro-oxidants. Specifically, we found that NADPH oxidases (NOXs) are regulated by Mcl-1 and that NOX4 expression in particular is a required step for CIS induction that is blocked by Mcl-1. Lastly, we illustrate that by preventing expression of NOX4, Mcl-1 limits its availability in the mitochondria, thereby lowering the production of mitochondrial ROS during CIS. Our studies not only define the essential role of Mcl-1 in chemoresistance, but also for the first time link a key pro-survival Bcl-2 family member with the NOX protein family, both of which have significant ramifications in cancer progression.

| S-EPMC5438639 | biostudies-other

Aldehydes from metal ion- and lipoxygenase-induced lipid peroxidation: detection by 1H-n.m.r. spectroscopy.

Project description:The modification of lipoproteins by reactive aldehydes formed via lipid peroxidation is thought to be a key process in the pathogenesis of atherosclerosis. We show that 1H-n.m.r. spectroscopy can readily be used to detect a variety of different aldehydes resulting from peroxidation of liposomes induced by Fenton's reagent or lipoxygenase, and aldehydes arising from copper-induced reactions of low-density lipoprotein. There is a clear contrast between the major aldehydic products arising from metal-ion- and lipoxygenase-induced reactions.

| S-EPMC1132142 | biostudies-other

Modulation of Oxidative Stress-Induced Senescence during Non-Alcoholic Fatty Liver Disease.

Project description:Non-alcoholic fatty liver disease is characterized by disturbed lipid metabolism and increased oxidative stress. These conditions lead to the activation of different cellular response mechanisms, including senescence. Cellular senescence constitutes an important response to injury in the liver. Recent findings show that chronic oxidative stress can induce senescence, and this might be a driving mechanism for NAFLD progression, aggravating the disturbance of lipid metabolism, organelle dysfunction, pro-inflammatory response and hepatocellular damage. In this context, the modulation of cellular senescence can be beneficial to ameliorate oxidative stress-related damage during NAFLD progression. This review focuses on the role of oxidative stress and senescence in the mechanisms leading to NAFLD and discusses the possibilities to modulate senescence as a therapeutic strategy in the treatment of NAFLD.

| S-EPMC9137746 | biostudies-literature

Therapy-Induced Senescence: An "Old" Friend Becomes the Enemy.

Project description:For the past two decades, cellular senescence has been recognized as a central component of the tumor cell response to chemotherapy and radiation. Traditionally, this form of senescence, termed Therapy-Induced Senescence (TIS), was linked to extensive nuclear damage precipitated by classical genotoxic chemotherapy. However, a number of other forms of therapy have also been shown to induce senescence in tumor cells independently of direct genomic damage. This review attempts to provide a comprehensive summary of both conventional and targeted anticancer therapeutics that have been shown to induce senescence in vitro and in vivo. Still, the utility of promoting senescence as a therapeutic endpoint remains under debate. Since senescence represents a durable form of growth arrest, it might be argued that senescence is a desirable outcome of cancer therapy. However, accumulating evidence suggesting that cells have the capacity to escape from TIS would support an alternative conclusion, that senescence provides an avenue whereby tumor cells can evade the potentially lethal action of anticancer drugs, allowing the cells to enter a temporary state of dormancy that eventually facilitates disease recurrence, often in a more aggressive state. Furthermore, TIS is now strongly connected to tumor cell remodeling, potentially to tumor dormancy, acquiring more ominous malignant phenotypes and accounts for several untoward adverse effects of cancer therapy. Here, we argue that senescence represents a barrier to effective anticancer treatment, and discuss the emerging efforts to identify and exploit agents with senolytic properties as a strategy for elimination of the persistent residual surviving tumor cell population, with the goal of mitigating the tumor-promoting influence of the senescent cells and to thereby reduce the likelihood of cancer relapse.

| S-EPMC7226427 | biostudies-literature

Therapy-induced senescence is a drug resistance mechanism in breast cancer

Project description:Here, we investigate therapy-induced senescence (TIS) as a reversible mechanism of drug resistance in breast cancer cells. High-dose doxorubicin treatment was used to induce TIS in four distinct breast cancer cell lines and the drug resistance/sensitivity pattern of parental and TIS cells were investigated using a panel of FDA-approved anticancer molecules. Proteome analysis confirmed the presence of the Senescence-Associated Secretory Phenotype (SASP), altered spliceosomal activity and proteins with significant role in immune evasion.

2024-11-19 | PXD058028 | JPOST Repository

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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