Microarray analysis of glioma cell lines : Temozolomide Sensitive vs. Resistant
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE193957 | GEO | 2023/03/01
REPOSITORIES: GEO
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Project description:The gene expression profiles were identified in glioblastoma cells treated with FAK inhibitor Y15, temozolomide alone or with combination of Y15 and Temozolomide DBTRG and U87 were treated with FAK inhibitor Y15 at 10 microM for 24 h; U87 cells were treated with Temozolomide 100 microM for 24 h and Y15+temozolomide at the same dose as each agent alone
2013-01-12 | E-GEOD-43452 | biostudies-arrayexpress
Project description:Introduction: Glioma stem cells isolated from human glioblastomas are resistant to radiation and cytotoxic chemotherapy and may drive tumor recurrence. Treatment efficacy may depend on the presence of glioma stem cells, expression of DNA repair enzymes such as methylguanine methyltransferase (MGMT), or transcriptome subtype. Methods: To model genetic alterations in the core signaling pathways of human glioblastoma, we induced conditional Rb knockout, Kras activation, and Pten deletion mutations in cortical murine astrocytes. Serial neurosphere culture, multi-lineage differentiation, and orthotopic transplantation were used to assess whether these mutations induced de-differentiation of cortical astrocytes into glioma stem cells. Efficacy of radiation and temozolomide was examined in vitro and in an allograft model in vivo. The effects of radiation on transcriptome subtype was examined by expression profiling. Results: G1/S-defective, Rb knockout astrocytes gained unlimited self-renewal and multi-lineage differentiation capacity, in both the presence and absence of Kras and Pten mutations. Only triple mutant astrocytes formed serially-transplantable glioblastoma allografts. Triple mutant astrocytes and allografts were sensitive to radiation, but expressed Mgmt and were resistant to temozolomide. Radiation induced a shift in transcriptome subtype of glioblastoma allografts from proneural to mesenchymal. Conclusion: A defined set of core signaling pathway mutations induces de-differentiation of cortical murine astrocytes into glioma stem cells. This non-germline genetically engineered mouse model mimics human proneural glioblastoma on histopathological, molecular, and treatment response levels. It may be useful in dissecting the genetic and cellular mechanisms of treatment resistance and developing more effective therapies.
2016-02-01 | GSE75589 | GEO
Project description:Introduction: Glioma stem cells isolated from human glioblastomas are resistant to radiation and cytotoxic chemotherapy and may drive tumor recurrence. Treatment efficacy may depend on the presence of glioma stem cells, expression of DNA repair enzymes such as methylguanine methyltransferase (MGMT), or transcriptome subtype. Methods: To model genetic alterations in the core signaling pathways of human glioblastoma, we induced conditional Rb knockout, Kras activation, and Pten deletion mutations in cortical murine astrocytes. Serial neurosphere culture, multi-lineage differentiation, and orthotopic transplantation were used to assess whether these mutations induced de-differentiation of cortical astrocytes into glioma stem cells. Efficacy of radiation and temozolomide was examined in vitro and in an allograft model in vivo. The effects of radiation on transcriptome subtype was examined by expression profiling. Results: G1/S-defective, Rb knockout astrocytes gained unlimited self-renewal and multi-lineage differentiation capacity, in both the presence and absence of Kras and Pten mutations. Only triple mutant astrocytes formed serially-transplantable glioblastoma allografts. Triple mutant astrocytes and allografts were sensitive to radiation, but expressed Mgmt and were resistant to temozolomide. Radiation induced a shift in transcriptome subtype of glioblastoma allografts from proneural to mesenchymal. Conclusion: A defined set of core signaling pathway mutations induces de-differentiation of cortical murine astrocytes into glioma stem cells. This non-germline genetically engineered mouse model mimics human proneural glioblastoma on histopathological, molecular, and treatment response levels. It may be useful in dissecting the genetic and cellular mechanisms of treatment resistance and developing more effective therapies.
2016-02-01 | GSE73262 | GEO
Project description:Overexpression of histone deacetylases (HDACs) in cancer commonly causes resistance to genotoxic based therapies. Here we report on the novel mechanism whereby overexpressed class I HDACs increase the resistance of glioblastoma cells to the SN1 methylating agent temozolomide (TMZ). The chemotherapeutic TMZ triggers the activation of the DNA damage response (DDR) in resistant glioma cells, leading to DNA lesion bypass and cellular survival. Mass spectrometry analysis revealed that the catalytic activity of class I HDACs stimulates the expression of the E3 ubiquitin ligase RAD18. Furthermore, the data show that RAD18 is part of the O6-methylguanine-induced DDR as TMZ induces the formation of RAD18 foci at sites of DNA damage. Downregulation of RAD18 by HDAC inhibition prevents glioma cells from activating the DDR upon TMZ exposure. Lastly, RAD18 or O6-methylguanine-DNA methyltransferase (MGMT) overexpression abolishes the sensitization effect of HDAC inhibition on TMZ-exposed glioma cells. Our study describes the mechanism whereby class I HDAC overexpression in glioma cells causes resistance to TMZ treatment. HDACs accomplish this by promoting the bypass of O6-methylguanine DNA lesions via enhancing RAD18 expression. It also provides a treatment option with HDAC inhibition to undermine this mechanism.
2022-04-01 | PXD028683 | Pride
Project description:Acquired resistance of temozolomide (TMZ) is one of the major obstacle of glioblastoma clinical treatment and the mechanism of TMZ resistance is still not very clear. In the presented research we show that deletion of rs16906252-associated MGMT enhancer in MGMT negative glioma cells induced increase sensitivity to temozolomide and combination of RNA-seq and Capture HiC identified several long-range target genes of rs16906252-associated MGMT enhancer. In addition, HiC data shows alterations of chromatin structures in glioma cells survived from high-dosage TMZ treatment and changes of TADs influence rs16906252-associated MGMT enhancer’s long-range regulations of target genes. Our study suggests rs16906252-associated MGMT enhancer regulates glioma cells’ TMZ sensitivity by long-range regulations of several target genes, which is a novel mechanism of regulation of TMZ sensitivity in glioma cells.
2020-04-02 | GSE129476 | GEO
Project description:Temozolomide (TMZ) resistance of glioma cells is currently a critical problem in glioma clinical treatment. In this study, we reveal a bivalent function of a super-enhancer RNA LINC02454 in modulating glioma cell sensitivity to TMZ via regulation of SORBS2 and DDR expression. LINC02454 increased TMZ sensitivity by maintaining 3D chromatin structure and promoting SORBS2 expression, but paradoxically decreased TMZ sensitivity by binding to the DDR1 locus and promoting DDR1 transcription. This study proposes a new regulatory mechanism governing glioma cell sensitivity to TMZ and provides new insights that may improve therapies against glioma.
2024-01-10 | GSE229600 | GEO
Project description:BACKGROUND: Glioma stem cells (GSCs) from human glioblastomas (GBMs) are resistant to radiation and chemotherapy and may drive recurrence. Treatment efficacy may depend on GSCs, expression of DNA repair enzymes such as methylguanine methyltransferase (MGMT), or transcriptome subtype. METHODS: To model genetic alterations in human GBM core signaling pathways, we induced Rb knockout, Kras activation, and Pten deletion mutations in cortical murine astrocytes. Neurosphere culture, differentiation, and orthotopic transplantation assays were used to assess whether these mutations induced de-differentiation into GSCs. Genome-wide chromatin landscape alterations and expression profiles were examined by formaldehyde-assisted isolation of regulatory elements (FAIRE) seq and RNA-seq. Radiation and temozolomide efficacy were examined in vitro and in an allograft model in vivo. Effects of radiation on transcriptome subtype were examined by microarray expression profiling. RESULTS: Cultured triple mutant astrocytes gained unlimited self-renewal and multilineage differentiation capacity. These cells harbored significantly altered chromatin landscapes that were associated with downregulation of astrocyte- and upregulation of stem cell-associated genes, particularly the Hoxa locus of embryonic transcription factors. Triple-mutant astrocytes formed serially transplantable glioblastoma allografts that were sensitive to radiation but expressed MGMT and were resistant to temozolomide. Radiation induced a shift in transcriptome subtype of GBM allografts from proneural to mesenchymal. CONCLUSION: A defined set of core signaling pathway mutations induces de-differentiation of cortical murine astrocytes into GSCs with altered chromatin landscapes and transcriptomes. This non-germline genetically engineered mouse model mimics human proneural GBM on histopathological, molecular, and treatment response levels. It may be useful for dissecting the mechanisms of treatment resistance and developing more effective therapies.
2016-01-31 | GSE59116 | GEO
Project description:FOXM1 plays a key role in M phase in normal cells and is overexpressed in human glioma. We found that FOXM1 deprivation could sensitize the glioma cells to TMZ chemotherapy. To find out the mechanistic regulation of FOXM1 in chemo-resistant genes, we used microarrays to select the potential genes regulated by FOXM1 which dominates in glioma chemo-resistance. U87 glioma cells were transiently transfected with none-target siRNA or FOXM1 siRNA. Total RNA were extracted after 48 hours and subjected to the microarray.
2012-08-10 | E-GEOD-40051 | biostudies-arrayexpress
Project description:An experimental lung metastasis assay was used to derive an invasive subline of U87 that is metastatic in mice. We used microarray analyses to find out over-represented gene ontologies that can explain the observed enhanced invasiveness of U87-2M1 cells. Early passage U87-2M1 cells and parental U87 glioma cells from ATCC were selected for RNA extraction and hybridization on microarray
2012-12-31 | E-GEOD-35169 | biostudies-arrayexpress
Project description:cell culture:The human glioma cell line U87MG was obtained from the Cell Resource Center, Peking Union Medical College (Beijing, China), and U251MG was acquired from the American Type Culture Collection (Manassas, VA). Temozolomide (TMZ) resistant U87MG cells (U87TR) and TMZ resistant U251MG cells (U251TR) of glioblastoma (GBM) sub-cell lines, were established through repetitive exposure to increasing TMZ concentrations in vitro in our laboratory. Cells were cultured in DMEM culture medium supplemented with 10% FBS with a standard humidified incubator under 5% CO2 at 37°C.
2023-05-01 | GSE151680 | GEO