Transcriptomics,Multiomics

Dataset Information

39

MGMT modulates glioblastoma angiogenesis and response to the tyrosine kinase inhibitor sunitinib


ABSTRACT: Angiogenesis inhibitors, such as sunitinib, represent a promising strategy to improve glioblastoma (GBM) tumor response. In this study, we used the O6-methylguanine methyltransferase (MGMT)-negative GBM cell line U87MG stably transfected with MGMT (U87/MGMT) to assess whether MGMT expression affects the response to sunitinib. We showed that the addition of sunitinib to standard therapy (temozolomide [TMZ] and radiation therapy [RT]) significantly improved the response of MGMT positive but not of MGMT-negative cells. Gene expression profiling revealed alterations in the angiogenic profile, as well as differential expression of several receptor tyrosine kinases targeted by sunitinib. MGMT-positive cells displayed higher levels of vascular endothelial growth factor receptor 1 (VEGFR-1) compared with U87/EV cells, whereas they displayed decreased levels of VEGFR-2. Depleting MGMT using O6-benzylguanine suggested that the expression of these receptors was directly related to the MGMT status. Also, we showed that MGMT expression was associated with a dramatic increase in the soluble VEGFR-1/VEGFA ratio, thereby suggesting a decrease in bioactive VEGFA and a shift towards an antiangiogenic profile. The reduced angiogenic potential of MGMT-positive cells is supported by: (i) the decreased ability of their secreted factors to induce endothelial tube formation in vitro and (ii) their low tumorigenicity in vivo compared with the MGMT-negative cells. Our study is the first to show a direct link between MGMT expression and decreased angiogenicity and tumorigenicity of GBM cells and suggests the combination of sunitinib and standard therapy as an alternative strategy for GBM patients with MGMT-positive tumors. RNA was isolated from parental U87 (U87_EV) and MGMT-transfected U87 (U87_MGMT) triplicate. Pairwise gene expression differences were compared between the two cell lines. Features selected had more than 2-fold up-or down-regulated (P values of >05, unpaired Student’s t-test with Bonferroni multiple testing correction) were identified. Database for annotation, visualization, and integrated discovery23 was used to identify enriched gene ontology (GO) biological themes.24 The GO data mining was conducted at a term specificity level 3.25 The EASE score was set at 0.05 and the minimum number of genes in a category was 5.

REANALYSED by: E-GEOD-40776

ORGANISM(S): Homo sapiens  

SUBMITTER: Kathryn Graham  Manik Chahal   Siham Sabri   Bassam Abdulkarim    

PROVIDER: E-GEOD-40776 | ArrayExpress | 2015-08-19

SECONDARY ACCESSION(S): GSE40776PRJNA174869

REPOSITORIES: GEO, ArrayExpress

altmetric image

Publications

MGMT modulates glioblastoma angiogenesis and response to the tyrosine kinase inhibitor sunitinib.

Chahal Manik M   Xu Yaoxian Y   Lesniak David D   Graham Kathryn K   Famulski Konrad K   Christensen James G JG   Aghi Manish M   Jacques Amanda A   Murray David D   Sabri Siham S   Abdulkarim Bassam B  

Neuro-oncology 20100223 8


Angiogenesis inhibitors, such as sunitinib, represent a promising strategy to improve glioblastoma (GBM) tumor response. In this study, we used the O(6)-methylguanine methyltransferase (MGMT)-negative GBM cell line U87MG stably transfected with MGMT (U87/MGMT) to assess whether MGMT expression affects the response to sunitinib. We showed that the addition of sunitinib to standard therapy (temozolomide [TMZ] and radiation therapy [RT]) significantly improved the response of MGMT-positive but not  ...[more]

Similar Datasets

2015-08-19 | E-GEOD-40776 | ExpressionAtlas
| GSE108098 | GEO
| GSE26600 | GEO
| GSE106159 | GEO
2014-06-02 | E-GEOD-26600 | ArrayExpress
2018-01-12 | E-MTAB-6326 | ArrayExpress
| GSE87535 | GEO
2012-01-05 | E-GEOD-26283 | ArrayExpress
2017-12-05 | E-MTAB-4969 | ArrayExpress
| GSE99181 | GEO