RAB38 Facilitates Energy Metabolism and Counteracts Cell Death in Glioblastoma Model Systems
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PROVIDER: PRJNA681872 | ENA |
REPOSITORIES: ENA
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Project description:Glioblastoma is a high-grade glial neoplasm with a patient survival of 12-18 months. Therefore, there is an urgent need for identification of novel therapeutic targets. RAB38 is a member of a family of small GTPase proteins and has been implicated in regulating cell proliferation and survival in tumors. The role of RAB38 in glioblastoma is unexplored. Here, we used human glioblastoma cell lines to test the hypothesis that RAB38 regulates glioblastoma growth. We found that genetic interference of RAB38 resulted in a marked decrease in glioblastoma growth, but not in astrocytes, through inhibition of proliferation and cell death induction accompanied by loss of mitochondrial membrane potential. Transcriptome analysis with subsequent gene set enrichment analysis (GSEA) showed that RAB38 silencing leads to changes in genes related to mitochondrial metabolism, intrinsic apoptosis (e.g. Bcl-xL) as well as a reduction in MYC targets. Consistently, rescue experiments demonstrated that loss of RAB38 causes reduction of glioblastoma viability through downregulation of both Bcl-xL and c-Myc, respectively. Moreover, RAB38 knock-down inhibited both glycolysis and oxidative phosphorylation. Consistently, interference with RAB38 enhanced cell death induced by BH3-mimetics. RAB38 antagonists are under development, but not yet clinically available. We found that FDA approved statins led to a rapid reduction in RAB38 protein expression, increased cell death and phenocopied some of the molecular changes elicited by loss of RAB38. In summary, our findings suggest that RAB38 is a potential therapeutic target for glioblastoma treatment.
2021-06-21 | GSE162444 | GEO
Project description:Pan and selective HDAC inhibition is synthetically lethal with TRAP1 inhibition in various model systems of glioblastoma, including patient derived xenograft (PDX) cells. Mechanistically, this occurs through several mechanisms, including the induction of metabolic stress by interference with tumor cell energy metabolism accompanied by modulation of pro- and anti-apoptotic Bcl-2 family proteins and the induction of a cell death with apoptotic features.
2020-05-13 | GSE150395 | GEO
Project description:Glioblastoma is a high-grade glial neoplasm with a patient survival of 12-18 months. Therefore, the identification of novel therapeutic targets is an urgent need. RAB38 is a GTPase protein implicated in regulating cell proliferation and survival in tumors. The role of RAB38 in glioblastoma is relatively unexplored. Here, we test the hypothesis that RAB38 regulates glioblastoma growth using human glioblastoma cell lines. We found that genetic interference of RAB38 resulted in a decrease in glioblastoma growth through inhibition of proliferation and cell death induction. Transcriptome analysis showed that RAB38 silencing leads to changes in genes related to mitochondrial metabolism and intrinsic apoptosis (e.g., Bcl-xL). Consistently, rescue experiments demonstrated that loss of RAB38 causes a reduction in glioblastoma viability through downregulation of Bcl-xL. Moreover, RAB38 knockdown inhibited both glycolysis and oxidative phosphorylation. Interference with RAB38 enhanced cell death induced by BH3-mimetics. RAB38 antagonists are under development, but not yet clinically available. We found that FDA-approved statins caused a rapid reduction in RAB38 protein levels, increased cell death, and phenocopied some of the molecular changes elicited by loss of RAB38. In summary, our findings suggest that RAB38 is a potential therapeutic target for glioblastoma treatment.
| S-EPMC8306361 | biostudies-literature
Project description:We analyzed the effects of enarodustat (JTZ-951; HIF stabilizer) on renal energy metabolism in streptozotocin-induced diabetic rat model. Transcriptome analysis of renal cortex revealed that genes related to fatty acid metabolism and amino acid metabolism were upregulated in diabetes and downregulated by enarodustat, whereas genes related to glucose metabolism were upregulated by enarodustat. Thus, HIF stabilization counteracts the renal energy metabolism alterations occurring in the early stages of diabetic kidney disease.
2020-05-14 | GSE131221 | GEO
Project description:We analyzed the effects of enarodustat (JTZ-951; HIF stabilizer) on renal energy metabolism in alloxan-induced diabetic mouse model. Transcriptome analysis of renal tissue revealed that genes related to fatty acid metabolism were upregulated in diabetes, whereas genes related to glucose metabolism were upregulated by enarodustat. In addition, genes related to amino acid metabolism were upregulated by diabetes and downregulated by enarodustat. Thus, HIF stabilization counteracts the renal energy metabolism alterations occurring in the early stages of diabetic kidney disease.
2020-05-14 | GSE139317 | GEO
Project description:Enarodustat, hypoxia-inducible factor stabilizer, counteracts the diabetic renal energy metabolism alterations in streptozotocin-induced diabetic rats
| PRJNA542935 | ENA
Project description:Necrosis is commonly found in various solid tumors and predicts worse outcome. Chronic ischemia can initiate tumor necrosis, but how the damaged tissue further expands is unclear. Previous studies found that neutrophils associate with necrosis and could contribute to necrosis development in glioblastoma (GBM) by transferring myeloperoxidase (MPO)-containing granules into tumor cells and inducing tumor cell ferroptosis. How the neutrophilic granule transfer occurs is unknown. Here, through an unbiased small molecule screen, we found that statins can inhibit neutrophil-induced tumor cell death by blocking the neutrophilic content transfer into tumor cells. Surprisingly, we found that neutrophils are engulfed by tumor cells before they are fragmented and release the MPO-containing contents in tumor cells. This process involves LC3-associated phagocytosis (LAP) and can be blocked by inhibiting the Vps34-UVRAG-containing PI3K complex. Inhibition of MPO or depletion of Vps34 in an orthotopic xenograft GBM mouse model reduced necrosis formation and allowed tumor-bearing mice to survive longer. Therefore, this study revealed that the neutrophilic granule transfer involves LAP-mediated neutrophil internalization, which then triggers tumor ferroptotic cell death in glioblastoma. Blocking this process may improve prognosis of GBM.
2024-04-29 | GSE263766 | GEO
Project description:LC3-associated phagocytosis of neutrophils trigger tumor ferroptotic cell death in glioblastoma
| PRJNA1099203 | ENA
Project description:Background: Newer 3D culturing approaches are a promising way to better mimic the in vivo tumor microenvironment and to study the interactions between the heterogeneous cell populations of glioblastoma multiforme. Like many other tumors, glioblastoma uses extracellular vesicles as an intercellular communication system to prepare surrounding tissue for invasive tumor growth. However, little is known about the effects of 3D culture on extracellular vesicles. The aim of this study was to comprehensively characterise extracellular vesicles in 3D organoid models and compare them to conventional 2D cell culture systems.Methods: Primary glioblastoma cells were cultured as 2D and 3D organoid models. Extracellular vesicles were obtained by precipitation and immunoaffinity, with the latter allowing targeted isolation of the CD9/CD63/CD81 vesicle subpopulation. Comprehensive vesicle characterisation was performed and miRNA expression profiles were generated by smallRNA-sequencing. In silico analysis of differentially regulated miRNAs was performed to identify mRNA targets and corresponding signaling pathways. The tumor cell media and extracellular vesicle proteome were analysed by high-resolution mass spectrometry.Results: We observed an increased concentration of extracellular vesicles in 3D organoid cultures. Differential gene expression analysis further revealed the regulation of twelve miRNAs in 3D tumor organoid cultures (with nine miRNAs down and three miRNAs upregulated). MiR-23a-3p, known to be involved in glioblastoma invasion, was significantly increased in 3D. MiR-7-5p, which counteracts glioblastoma malignancy, was significantly decreased. Moreover, we identified four miRNAs (miR- 323a-3p, miR-382-5p, miR-370-3p, miR-134-5p) located within the DLK1-DIO3 domain, a cancer associated genomic region, suggesting a possible importance of this region in glioblastoma progression. Overrepresentation analysis identified alterations of extracellular vesicle cargo in 3D organoids, including representation of several miRNA targets and proteins primarily implicated in the immune response.Conclusion: Our results show that 3D glioblastoma organoid models secrete extracellular vesicles with an altered cargo compared to corresponding conventional 2D cultures. Extracellular vesicles from 3D cultures were found to contain signaling molecules associated with the immune regulatory signaling pathways and as such could potentially change the surrounding microenvironment towards tumor progression and immunosuppressive conditions. These findings suggest the use of 3D glioblastoma models for further clinical biomarker studies as well as investigation of new therapeutic options.
2024-04-09 | PXD047328 | Pride
Project description:ISG15 counteracts Listeria monocytogenes infection
| PRJEB9655 | ENA