Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Expression data from rat tumors formed by 9L.EV or 9L.EGFRvIII cells

ABSTRACT: Analysis of rat tumor xenografts revealed genes that are upregulated in tumors expressing EGFRvIII 12 rats received intracranial injections of 9L cells expressing EGFRvIII or an empty vector control. Three weeks after implantation and subsequent growth, tumors were aseptically removed, processed for RNA extraction, and analyzed for gene expression profiling using the RatRef12 Illumina chip array. We compared the average expression of all the transcripts between EGFRvIII-expressing and empty vector control tumors.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Matthew Lazzara

PROVIDER: E-GEOD-51147 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Sprouty2 Drives Drug Resistance and Proliferation in Glioblastoma.

Walsh Alice M AM Kapoor Gurpreet S GS Buonato Janine M JM Mathew Lijoy K LK Bi Yingtao Y Davuluri Ramana V RV Martinez-Lage Maria M Simon M Celeste MC O'Rourke Donald M DM Lazzara Matthew J MJ

Molecular cancer research : MCR 20150501 8

<h4>Unlabelled</h4>Glioblastoma multiforme (GBM) is notoriously resistant to therapy, and the development of a durable cure will require the identification of broadly relevant regulators of GBM cell tumorigenicity and survival. Here, we identify Sprouty2 (SPRY2), a known regulator of receptor tyrosine kinases (RTK), as one such regulator. SPRY2 knockdown reduced proliferation and anchorage-independent growth in GBM cells and slowed xenograft tumor growth in mice. SPRY2 knockdown also promoted ce ...[more]

PMID: 25934697

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Project description:Background: EGFRvIII is a mutant form of the epidermal growth factor receptor gene (EGFR) that lacks exons 2-7. The resulting protein does not bind to ligands and is constitutively activated. The expression of EGFRvIII is likely confined to various types of cancer, particularly glioblastomas. Although an anti-EGFRvIII vaccine is of great interest, low-molecular-weight substances are needed to obtain better therapeutic efficacy. Thus, the purpose of this study is to identify low molecular weight substances that can suppress EGFRvIII-dependent transformation. Methods: We constructed a new throughput screening system and searched for substances that decreased cell survival of NIH3T3/EGFRvIII spheres under 3-dimensional (3D)-culture conditions, but retained normal NIH3T3 cell growth under 2D-culture conditions. In vivo activity was examined using a mouse transplantation model, and derivatives were chemically synthesized. Functional characterization of the candidate molecules was investigated using an EGFR kinase assay, immunoprecipitation, western blotting, microarray analysis,quantitative polymerase chain reaction analysis, and measurement of lactate and ATP synthesis. Results: In the course of screening 30,000 substances, a reagent, âErtredin,â was found to inhibit anchorage-independent 3D growth of sphere-forming cells transfected with EGFRvIII cDNA. Ertredin also inhibited sphere formation in cells expressing wild-type EGFR in the presence of EGF. However, it did not affect anchorage-dependent 2D growth of parental NIH3T3 cells. The 3D-growth-inhibitory activity of some derivatives, including those with new structures, was similar to Ertredin. Furthermore, we demonstrated that Ertredin suppressed tumor growth in an allograft transplantation mouse model injected with EGFRvIII- or wild-type EGFR-expressing cells; a clear toxicity to host animals was not observed. Functional characterization of Ertredin in cells expressing EGFRvIII indicated that it stimulated EGFRvIII ubiquitination, suppressed both oxidative phosphorylation and glycolysis under 3D conditions, and promoted cell apoptosis. Conclusion: We developed a high throughput screening method based on anchorage-independent sphere formation induced by EGFRvIII-dependent transformation. In the course of screening, we identified Ertredin, which inhibited anchorage-independent 3D growth and tumor formation in nude mice. Functional analysis suggests that Ertredin suppresses both mitochondrial oxidative phosphorylation and cytosolic glycolysis in addition to promoting EGFRvIII degradation, and stimulates apoptosis in sphere-forming, EGFRvIII-overexpressing cells. Patterns of gene expression in cells treated with Ertredin (sample 2), rotenone (sample 3), and AG1478 (sample 4) were compared with vehicle-control cells (sample 1).

Dataset Information

Expression data from rat tumors formed by 9L.EV or 9L.EGFRvIII cells

Publications

Sprouty2 Drives Drug Resistance and Proliferation in Glioblastoma.

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