Correction to: Lipolytic inhibitor G0S2 modulates glioma stem-like cell radiation response.
Ontology highlight
ABSTRACT:
SUBMITTER: Wang Y
PROVIDER: S-EPMC6633653 | biostudies-literature | 2019 Jul
REPOSITORIES: biostudies-literature
Publications
Correction to: Lipolytic inhibitor G0S2 modulates glioma stem-like cell radiation response.
Wang Yinfang Y Hou Yanli Y Zhang Weiwei W Alvarez Angel A AA Bai Yongrui Y Hu Bo B Cheng Shi-Yuan SY Yang Kun K Li Yanxin Y Feng Haizhong H
Journal of orthopaedic surgery and research 20190716 1
In the original publication of this article [1], the Gene Expression Omnibus (GEO) accession code GSE79772 is wrong. The correct accession code should be GSE86213. ...[more]
Similar Datasets
Project description:In the original publication of this article [1], the Gene Expression Omnibus (GEO) accession code GSE79772 is wrong. The correct accession code should be GSE86213.
| S-EPMC6661739 | biostudies-literature
Project description:BACKGROUND:Ionizing radiation (IR) therapy is the standard first-line treatment for newly diagnosed patients with glioblastoma (GBM), the most common and malignant primary brain tumor. However, the effects of IR are limited due to the aberrant radioresistance of GBM. METHODS:Transcriptome analysis was performed using RNA-seq in radioresistant patient-derived glioma stem-like cells (GSCs). Survival of glioma patient and mice bearing-brain tumors was analyzed by Kaplan-Meier survival analysis. Lipid droplet and ?-H2AX foci-positive cells were evaluated using immunofluorescence staining. RESULTS:Lipolytic inhibitor G0/G1 switch gene 2 (G0S2) is upregulated in radioresistant GSCs and elevated in clinical GBM. GBM patients with high G0S2 expression had significantly shorter overall survival compared with those with low expression of G0S2. Using genetic approaches targeting G0S2 in glioma cells and GSCs, we found that knockdown of G0S2 promoted lipid droplet turnover, inhibited GSC radioresistance, and extended survival of xenograft tumor mice with or without IR. In contrast, overexpression of G0S2 promoted glioma cell radiation resistance. Mechanistically, high expression of G0S2 reduced lipid droplet turnover and thereby attenuated E3 ligase RNF168-mediated 53BP1 ubiquitination through activated the mechanistic target of rapamycin (mTOR)-ribosomal S6 kinase (S6K) signaling and increased 53BP1 protein stability in response to IR, leading to enhanced DNA repair and glioma radioresistance. CONCLUSIONS:Our findings uncover a new function for lipolytic inhibitor G0S2 as an important regulator for GSC radioresistance, suggesting G0S2 as a potential therapeutic target for treating gliomas.
| S-EPMC6451284 | biostudies-literature
Project description:Biochemical and cell-based studies have identified the G0S2 (G0/G1 switch gene 2) as a selective inhibitor of the key intracellular triacylglycerol hydrolase, adipose triglyceride lipase. To better understand the physiological role of G0S2, we constructed an adipose tissue-specific G0S2 transgenic mouse model. In comparison with wild type animals, the transgenic mice exhibited a significant increase in overall fat mass and a decrease in peripheral triglyceride accumulation. Basal and adrenergically stimulated lipolysis was attenuated in adipose explants isolated from the transgenic mice. Following fasting or injection of a ?3-adrenergic agonist, in vivo lipolysis and ketogenesis were decreased in G0S2 transgenic mice when compared with wild type animals. Consequently, adipose overexpression of G0S2 prevented the "switch" of energy substrate from carbohydrates to fatty acids during fasting. Moreover, G0S2 overexpression promoted accumulation of more and larger lipid droplets in brown adipocytes without impacting either mitochondrial morphology or expression of oxidative genes. This phenotypic change was accompanied by defective cold adaptation. Furthermore, feeding with a high fat diet caused a greater gain of both body weight and adiposity in the transgenic mice. The transgenic mice also displayed a decrease in fasting plasma levels of free fatty acid, triglyceride, and insulin as well as improved glucose and insulin tolerance. Cumulatively, these results indicate that fat-specific G0S2 overexpression uncouples adiposity from insulin sensitivity and overall metabolic health through inhibiting adipose lipolysis and decreasing circulating fatty acids.
| S-EPMC3900941 | biostudies-literature
Project description: Not available
| S-EPMC4529295 | biostudies-literature
Project description:Despite the availability of hundreds of cancer drugs, there is insufficient data on the efficacy of these drugs on the extremely heterogeneous tumor cell populations of glioblastoma (GBM).The PKIS of 357 compounds was initially evaluated in 15 different GSC lines which then led to a more focused screening of the 21 most highly active compounds in 11 unique GSC lines using HTS screening for cell viability. We further validated the HTS result with the second-generation PLK1 inhibitor volasertib as a single agent and in combination with ionizing radiation (IR). In vitro studies showed that volasertib inhibited cell viability, and high levels of the anti-apoptotic protein Bcl-xL expression were highly correlated with volasertib resistance. Volasertib sensitized GSCs to radiation therapy by enhancing G2/M arrest and by inducing apoptosis. Colony-formation assay demonstrated that volasertib plus IR synergistically inhibited colony formation. In intracranial xenograft mouse models, the combination of volasertib and radiation significantly inhibited GSC tumor growth and prolonged median survival compared with radiation treatment alone due to inhibition of cell proliferation, enhancement of DNA damage, and induction of apoptosis.Our results reinforce the potential therapeutic efficacy of volasertib in combination with radiation for the treatment of GBM.We used high-throughput screening (HTS) to identify drugs, out of 357 compounds in the published Protein Kinase Inhibitor Set, with the greatest efficacy against a panel of glioma stem cells (GSCs), which are representative of the classic cancer genome atlas (TCGA) molecular subtypes.
| S-EPMC5828226 | biostudies-literature
Project description:The high incidence of glioblastoma recurrence necessitates additional therapeutic strategies. Heterogeneous populations of cells, including glioma stem cells (GSC) have been implicated in disease recurrence. GSCs are able to survive irradiation and temozolomide (TMZ) treatment due to upregulation of DNA damage pathways. One potential strategy to target treatment-resistant tumor populations may be via the integrated stress response (ISR). Modulation of the ISR pathway also allows for sensitization of treatment-resistant cells to TRAIL. We generated a novel cell-based death receptor assay to identify potent inducers of ISR-dependent DR5 expression. We used this assay to screen compounds from three commercially available libraries, and identified 1-benzyl-3-cetyl-2-methylimidazolium iodide (NH125) as a potent inducer of DR5 expression. NH125 engages the EIF2α-ATF4-CHOP axis culminating in DR5 expression at low micromolar doses. Expression of CHOP plays a critical role in NH125-mediated TRAIL synergy. Treatment of GSC with NH125 produces a marked reduction in viability when compared with other cell lines. NH125-treated GSC also synergize with lower doses of TRAIL when compared with all other cell lines tested. Transcriptional analysis of NH125-treated GSC uncovers a unique profile that involves activation of ISR and GADD45 pathways. Treatment of GSC xenografts with encapsulated PEG-PCL-NH125 leads to a sustained decrease in tumor volume. IMPLICATIONS: Taken together, these data suggest that engaging the ISR pathway represents a promising strategy to target treatment refractory GSC that have been implicated in glioblastoma recurrence.
| S-EPMC8797269 | biostudies-literature
Project description:Tumor regression in sites distant to the irradiated field are thought to be associated with emission of damage-associated molecular patterns (DAMPs) molecules and generation of immunogenic cell death (ICD). Glioma stem cells (GSCs) are resistant to high doses of radiation, and ultimately select the outgrowth of a more aggressive tumor. This study showed high-dose IR triggered fewer DAMPs molecules exposure and release in GSCs comparing to matched non-GSCs. Downregulation of binding immunoglobulin protein (Bip) promoted IR-mediated endoplasmic reticulum stress to generate DAMPs molecules by PERK and IRE1-α phosphorylation, and increased dendritic cells mature and effector T lymphocytes activation. GSCs treated with Bip knockdown and IR efficiently prevented tumor generation, and reduced post-radiotherapy tumor recurrence. These data suggest that Bip plays a critical role in inhibition of IR-induced ICD in GSCs, and Bip inhibition may be a promising strategy on adjuvant therapy by ameliorating tumor immune microenvironment.
| S-EPMC7508950 | biostudies-literature
Project description:Unresectable glioblastoma (GBM) cells in the invading tumor edge can act as seeds for recurrence. The molecular and phenotypic properties of these cells remain elusive. Here, we report that the invading edge and tumor core have two distinct types of glioma stem-like cells (GSCs) that resemble proneural (PN) and mesenchymal (MES) subtypes, respectively. Upon exposure to ionizing radiation (IR), GSCs, initially enriched for a CD133+ PN signature, transition to a CD109+ MES subtype in a C/EBP-β-dependent manner. Our gene expression analysis of paired cohorts of patients with primary and recurrent GBMs identified a CD133-to-CD109 shift in tumors with an MES recurrence. Patient-derived CD133-/CD109+ cells are highly enriched with clonogenic, tumor-initiating, and radiation-resistant properties, and silencing CD109 significantly inhibits these phenotypes. We also report a conserved regulation of YAP/TAZ pathways by CD109 that could be a therapeutic target in GBM.
| S-EPMC6594377 | biostudies-literature
Project description:Intestinal crypt progenitor/stem (ICPS) cell apoptosis and vascular endothelial cell apoptosis are responsible for the initiation and development of ionizing radiation (IR)-evoked gastrointestinal syndrome. The signaling mechanisms underlying IR-induced ICPS cell apoptosis remain largely unclear. Our findings provide evidence that ?-arrestin-2 (?arr2)-mediated ICPS cell apoptosis is crucial for IR-stimulated intestinal injury. ?Arr2-deficient mice exhibited decreased ICPS cell and intestinal Lgr5(+) (leucine-rich repeat-containing G-protein-coupled receptor 5-positive) stem cell apoptosis, promoted crypt proliferation and reproduction, and protracted survival following lethal doses of radiation. Radioprotection in the ICPS cells isolated from ?arr2-deficient mice depended on prolonged nuclear factor-?B (NF-?B) activation via direct interaction of ?arr2 with I?B? and subsequent inhibition of p53-upregulated modulator of apoptosis (PUMA)-mediated mitochondrial dysfunction. Unexpectedly, ?arr2 deficiency had little effect on IR-induced intestinal vascular endothelial cell apoptosis in mice. Consistently, ?arr2 knockdown also provided significant radioresistance by manipulating NF-?B/PUMA signaling in Lgr5(+) cells in vitro. Collectively, these observations show that targeting the ?arr2/NF-?B/PUMA novel pathway is a potential radiomitigator for limiting the damaging effect of radiotherapy on the gastrointestinal system. Significance statement: acute injury to the intestinal mucosa is a major dose-limiting complication of abdominal radiotherapy. The issue of whether the critical factor for the initiation of radiation-induced intestinal injury is intestinal stem cell apoptosis or endothelial cell apoptosis remains unresolved. ?Arrs have recently been found to be multifunctional adaptor of apoptosis. Here, we found that ?-arrestin-2 (?arr2) deficiency was associated with decreased radiation-induced ICPS cell apoptosis, which prolonged survival in abdominally irradiated mice. Moreover, ?arr2 deficiency-mediated intestinal progenitor/stem cell radioprotection relied on protracted NF-?B activation and subsequent suppression of PUMA induction. Our results suggest that ICPS cell apoptosis is the factor involved in the initiation and development of radiation-induced gastrointestinal syndrome. ?Arr2 is a potential target for lessening radiation-induced ICPS cell apoptosis.
| S-EPMC5072429 | biostudies-literature
Project description:Despite advances in novel therapeutic approaches for the treatment of glioblastoma (GBM), the median survival of 12-14 months has not changed significantly. Therefore, there is an imperative need to identify molecular mechanisms that play a role in patient survival. Here, we analyzed the expression and functions of a novel lncRNA, TALNEC2 that was identified using RNA seq of E2F1-regulated lncRNAs. TALNEC2 was localized to the cytosol and its expression was E2F1-regulated and cell-cycle dependent. TALNEC2 was highly expressed in GBM with poor prognosis, in GBM specimens derived from short-term survivors and in glioma cells and glioma stem cells (GSCs). Silencing of TALNEC2 inhibited cell proliferation and arrested the cells in the G1\S phase of the cell cycle in various cancer cell lines. In addition, silencing of TALNEC2 decreased the self-renewal and mesenchymal transformation of GSCs, increased sensitivity of these cells to radiation and prolonged survival of mice bearing GSC-derived xenografts. Using miRNA array analysis, we identified specific miRNAs that were altered in the silenced cells that were associated with cell-cycle progression, proliferation and mesenchymal transformation. Two of the downregulated miRNAs, miR-21 and miR-191, mediated some of TALNEC2 effects on the stemness and mesenchymal transformation of GSCs. In conclusion, we identified a novel E2F1-regulated lncRNA that is highly expressed in GBM and in tumors from patients of short-term survival. The expression of TALNEC2 is associated with the increased tumorigenic potential of GSCs and their resistance to radiation. We conclude that TALNEC2 is an attractive therapeutic target for the treatment of GBM.
| S-EPMC5458248 | biostudies-literature