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Time-dependent expressed markers and their characterization for premature senescence induced by ionizing radiation in MCF7

ABSTRACT: Recently, senescence has been suggested as a defense mechanism to block sporadic induction of cancer cells. Radiation treatment induces proliferating cancer cells to turn into non-proliferating senescent cells in vitro. To characterize transcriptional reprogramming after radiation treatment, we measured the gene expression profiles of MCF7 at different time points after treatment. In these experiments, we found that IR induced premature senescence in MCF7 cells, and IR treatment resulted in significant changes in the expression of 305 marker genes (less than 1% FDR), which were strongly correlated (|r|>0.9) with IR treatment in a time-dependent manner. Functional analysis of these markers indicated that the dynamics of cytoskeletal structure and lysosomal activity gradually increased. The expression of marker genes for modulator proteins, that were responsible for the dynamics of actin stress fibers and focal adhesion, displayed a particularly strong positive correlation with senescence-associated (SA) morphological changes through time. We also observed a strong induction of genes related to lysosomal metabolic activity, which was accompanied by an increase in the number of SA-beta-Gal positive cells. However, the expression of genes for the cell cycle progression, the post-transcription and the translation activities gradually decreased after radiation treatment. Especially, we observed clear cell cycle arrest specifically at the S and G2/M phases with consistent down-regulation of genes for microtubule assembly/disassembly or spindle biogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE21748 | GEO | 2010/05/31

SECONDARY ACCESSION(S): PRJNA127335

REPOSITORIES: GEO

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Time-dependent expressed markers and their characterization for premature senescence induced by ionizing radiation in MCF7

Project description:Recently, senescence has been suggested as a defense mechanism to block sporadic induction of cancer cells. Radiation treatment induces proliferating cancer cells to turn into non-proliferating senescent cells in vitro. To characterize transcriptional reprogramming after radiation treatment, we measured the gene expression profiles of MCF7 at different time points after treatment. In these experiments, we found that IR induced premature senescence in MCF7 cells, and IR treatment resulted in significant changes in the expression of 305 marker genes (less than 1% FDR), which were strongly correlated (|r|>0.9) with IR treatment in a time-dependent manner. Functional analysis of these markers indicated that the dynamics of cytoskeletal structure and lysosomal activity gradually increased. The expression of marker genes for modulator proteins, that were responsible for the dynamics of actin stress fibers and focal adhesion, displayed a particularly strong positive correlation with senescence-associated (SA) morphological changes through time. We also observed a strong induction of genes related to lysosomal metabolic activity, which was accompanied by an increase in the number of SA-beta-Gal positive cells. However, the expression of genes for the cell cycle progression, the post-transcription and the translation activities gradually decreased after radiation treatment. Especially, we observed clear cell cycle arrest specifically at the S and G2/M phases with consistent down-regulation of genes for microtubule assembly/disassembly or spindle biogenesis. Gene expression profiles were obtained from human MCF7 cells after ionizing radiation (6 Gy) at day 0 (no ionizing radiation), day 1 (after ionizing radiation), day 2, day 3, and day 4.

2010-06-08 | E-GEOD-21748 | biostudies-arrayexpress

Senescent Characteristics of Human Corneal Endothelial Cells upon Ultraviolet-A Exposure

Project description:Purpose: The objective of this study was to investigate the senescent phenotypes of human corneal endothelial cells (hCEnCs) upon treatment with ultraviolet (UV)-A. Methods: We assessed cell morphology, senescence-associated β-galactosidase (SA-β-gal) activity, cell proliferation and expression of senescence markers (p16 and p21) in hCEnCs exposed to UV-A radiation, and senescent hCEnCs induced by ionizing radiation (IR) were used as positive controls. We performed RNA sequencing and proteomics analysis to compare gene and protein expression profiles between UV-A- and IR-induced senescent hCEnCs, and we also compared the results to non-senescent hCEnCs. Results: Cells exposed to 5 J/cm2 of UV-A or to IR exhibited typical senescent phenotypes, including enlargement, increased SA-β-gal activity, decreased cell proliferation and elevated expression of p16 and p21. RNA-Seq analysis revealed that 83.9% of the genes significantly upregulated and 82.6% of the genes significantly downregulated in UV-A-induced senescent hCEnCs overlapped with the genes regulated in IR-induced senescent hCEnCs. Proteomics also revealed that 93.8% of the proteins significantly upregulated in UV-A-induced senescent hCEnCs overlapped with those induced by IR. In proteomics analyses, senescent hCEnCs induced by UV-A exhibited elevated expression levels of several factors part of the senescence-associated secretory phenotype. Conclusion: In this study, where senescence was induced by UV-A, a more physiological stress for hCEnCs compared to IR, we determined that UV-A modulated the expression of many genes and proteins typically altered upon IR treatment, a more conventional method of senescence induction, even though UV-A also modulated specific pathways unrelated to IR.

2024-05-17 | GSE250224 | GEO

Gene expression response to high radiation treatment in MCF7 breast cancer cell line

Project description:Intraoperative radiotherapy (IOERT) is a high radiation therapeutic technique which administers a single high dose of ionizing radiation (IR) immediately after surgical tumor removal in order to destroy the residual cancer cells in the site at high risk for recurrence. IR is able to regulate several genes and factors involved in cell-cycle progression, survival and/or cell death, DNA repair and inflammation modulating an intracellular response radiation dependent producing an imbalance in cell fate decision. In this study, we examined changes in gene expression in MCF7 breast cancer cell line exposed to 9Gy and 23Gy high single dose of IR delivered by IOERT. Changes in gene expression in MCF7 breast cancer cell line exposed to 9Gy and 23Gy high single dose of IR (named MCF7_9Gy and MCF7_23Gy respectively), were analyzed as two-color hybridizations using Agilent Technologies whole human genome 4x44K microarrays

2015-06-11 | E-GEOD-63667 | biostudies-arrayexpress

Gene expression response to high radiation treatment in MCF7 breast cancer cell line

2015-06-11 | GSE63667 | GEO

High resolution profiling of gene expression during probenazole (PBZ) treatment in Arabidopsis

Project description:Leaf senescence is a developmentally programmed event, which is also regulated by several phytohormones such as SA. SA has been shown to regulate the expression of many genes during leaf senescence, the fact that the mutants defective in SA biosynthesis and signaling have negligible senescence-related phenotypes makes it difficult to evaluate the exact role of SA in regulating leaf senescence. We have previously shown that probenazole (PBZ) is able to induce endogenous SA biosynthesis when applied by root drenching. We also detected an accelerated leaf yellowing phenotype about two weeks after PBZ treatment. Analysis of PBZ response genes identifies several MAPKs genes may be involved in SA induced senescence signaling pathway. We used microarrays to detail the global programme of gene expression underlying probenazole (PBZ) treatment in Arabidopsis and identified distinct classes of MAPKs genes during this process.

2017-09-02 | GSE72636 | GEO

Ripk3 signaling regulates the number and function of HSCs during stress and represses radiation-induced leukemia in mice

Project description:We found that Ripk3 signaling selectively regulates both the number and function of hematopoietic stem cells (HSCs) during stress conditions and inhibits ionizing radiation (IR)-induced leukemia development in mice. During serial transplantation, which stimulates a chronic Ripk3 activation in HSCs, Ripk3 promotes the loss of HSCs via Mlkl-mediated necroptosis and impairs HSC function by inducing ROS-p38-p16 mediated senescence. In response to 6Gy of IR, which induces the activation of p53-p21-mediated cell cycle arrest/senescence in HSCs, Ripk3 is required for the activation of NF-κB and permits the survival of the senescent cells. However, in response to multiple low doses of IR (1.75 × 4), Ripk3 signaling inhibits leukemia development by inducing ROS-p38-p16-mediated senescence and repressing Ire1α-Xbp1-Dnajb8 UPR fitness in pre-leukemic stem cells (pre-LSCs) and also inducing Mlkl-dependent clearance of pre-LSCs. Mlkl deletion prevents IR-induced loss of HSCs and slightly accelerates leukemia development in mice, while Ripk3 deletion represses both necroptotic and senescence signals in pre-LSCs and significantly accelerates IR-induced leukemia development. Our study suggests that immediately after high dose IR, temporal inhibition of Ripk3-NF-κB signaling might help to prevent long-term residual damage (LT-RDs) in bone marrow by eliminating the IR-induced senescent HSCs. However, in response to low dose radiation, induced activation of Ripk3 signaling at the pre-leukemia stage might help to prevent the accumulation of mutant HSCs and the development of leukemia.

2022-06-29 | GSE139143 | GEO

Surfaceome analysis of extracellular vesicles from senescent cells uncovers uptake repressor DPP4

Project description:Senescent cells are beneficial for repairing acute tissue damage but are harmful when they accumulate in tissues, as occurs with advancing age. Senescence-associated extracellular vesicles (S-EVs) can mediate cell-to-cell communication and export intracellular content to the microenvironment of aging tissues. Here, we studied the uptake of EVs from senescent cells (S-EVs) relative to proliferating cells (P-EVs). Interestingly, P-EVs were readily taken up by other proliferating cells (fibroblasts and cervical cancer cells) while S-EVs were not; by contrast, macrophages selectively engulfed all EVs (P-EVs, S-EVs). We thus investigated the surface proteome (surfaceome) of P-EVs relative to S-EVs derived from cells that had reached senescence via replicative exhaustion, exposure to ionizing radiation, or treatment with etoposide. We discovered that relative to P-EVs, S-EVs from all senescence models were enriched in proteins DPP4, ANXA1, ANXA6, S10AB, AT1A1, and EPHB2. Among them, DPP4 was found to dictate selective uptake by proliferating cells, as ectopic overexpression of DPP4 in HeLa cells rendered DPP-expressing EVs that were no longer taken up by other proliferating cells. We propose that DPP4 on the surface of S-EVs makes these EVs refractory to internalization by proliferating cells, advancing our knowledge of the impact of senescent cells in aging-associated processes.

2022-10-09 | MSV000090503 | MassIVE

Graded regulation of cellular quiescence depth between proliferation and senescence by a lysosomal dimmer switch

Project description:The reactivation of quiescent cells to proliferate is fundamental to tissue repair and homeostasis in the body. Often referred to as the G0 state, quiescence is however not a uniform state but with graded depth. Shallow quiescent cells exhibit a higher tendency to revert to proliferation than deep quiescent cells, while deep quiescent cells are still fully reversible under physiological conditions, distinct from senescent cells. Cellular mechanisms underlying the control of quiescence depth and the connection between quiescence and senescence are poorly characterized, representing a missing link in our understanding of tissue homeostasis and regeneration. Here we measured transcriptome changes as rat embryonic fibroblasts moved from shallow to deep quiescence over time in the absence of growth signals. We found that lysosomal gene expression was significantly upregulated in deep quiescence, and partially compensated for gradually reduced autophagy flux. Reducing lysosomal function drove cells progressively deeper into quiescence and eventually into a senescence-like irreversibly arrested state; increasing lysosomal function, by lowering oxidative stress, progressively pushed cells into shallower quiescence. That is, lysosomal function modulates graded quiescence depth between proliferation and senescence as a dimmer switch. Lastly, we found that a gene expression signature developed by comparing deep and shallow quiescence in fibroblasts can correctly classify a wide array of senescent and aging cell types in vitro and in vivo, suggesting that while quiescence is generally considered to protect cells from irreversible arrest of senescence, quiescence deepening likely represents a common transition path from cell proliferation to senescence, related to aging.

2019-10-11 | GSE124109 | GEO

Chemotherapy-induced cellular senescence is characterized by aberrant lipid regulation and lipid peroxidation

Project description:As normal cells approach their proliferative limit, they arrest to undergo replicative senescence, displaying large cell size, flat morphology and activation of senescence-associated beta-galactosidase (SA-b-Gal). A subset of normal or tumor cells exposed in vitro or in vivo to chemotherapy agents such as etoposide perform a related response with a similar cellular phenotype dubbed therapy-induced senescence (TIS). High cellular heterogeneity in samples including TIS cells can impede confident determination of senescence-specific factors, frustrating discovery of markers and targets for functional analysis. As a TIS study model, we treated murine melanoma cells with the chemotherapeutic etoposide, applied a live-cell fluorescent SA-b-Gal senescence assay, and utilized fluorescence-activated cell sorting (FACS) to enrich TIS cells. Enriched senescent cell samples were subjected to mass spectrometry and label-free quantitative proteomics analysis, alongside proliferating and quiescent cell samples. Systems biology analysis revealed that senescent cells overexpress proteins and pathways regulating glycolipid processing, lipid metabolism, and lipid peroxidation. Senescence-associated activation of numerous glycosidases was observed, along with elevated cell surface expression of several major lipid regulatory proteins. Senescent cells were found to contain abundant lipid droplets and to import various types of extracellular lipids in correlation with extent of SA-b-Gal expression, and tumor cells were observed to spontaneously senesce in the presence of excess ceramide or triglycerides. Redox-induced lipid peroxidation, resulting in accumulation of cellular reactive aldehydes and consequent expression of aldehyde detoxification enzymes, was observed to be a key feature of TIS induced by three DNA-damaging chemotherapeutics.

2017-11-06 | PXD006216 | Pride

Wnt5A promotes an adaptive, senescent-like stress response, while continuing to drive invasion in melanoma cells.

Project description:We have previously shown that Wnt5A drives invasion in melanoma. We have also shown that Wnt5A promotes resistance to therapy designed to target the BRAF(V600E) mutation in melanoma. Here, we show that melanomas characterized by high levels of Wnt5A respond to therapeutic stress by increasing p21 and expressing classical markers of senescence, including positivity for senescence-associated ?-galactosidase (SA-?-gal), senescence-associated heterochromatic foci (SAHF), H3K9Me chromatin marks, and PML bodies. We find that despite this, these cells retain their ability to migrate and invade. Further, despite the expression of classic markers of senescence such as SA-?-gal and SAHF, these Wnt5A-high cells are able to colonize the lungs in in vivo tail vein colony-forming assays. This clearly underscores the fact that these markers do not indicate true senescence in these cells, but instead an adaptive stress response that allows the cells to evade therapy and invade. Notably, silencing Wnt5A reduces expression of these markers and decreases invasiveness. The combined data point to Wnt5A as a master regulator of an adaptive stress response in melanoma, which may contribute to therapy resistance. To better understand the molecular mechanisms governing the response of highly invasive cells to IR as compared to that of poorly invasive cells, we performed microarray analysis of both poorly and highly invasive cells at early and late timepoints after irradiation. Cells were treated with y-irradiation, and RNA was taken at 1 hour, 24 hours and 5 days after irradiation. Microarray analysis was performed using Illumina Human HT-12 ver3 expression arrays, and each time point was compared to RNA from untreated cells.

2015-08-07 | E-GEOD-50004 | biostudies-arrayexpress

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