Glioma stem cell treatment with MELK-signaling inhibitors
Transcriptomics Dataset
FAIR Metrics
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General Information
AccessionGSE50227
TitleGlioma stem cell treatment with MELK-signaling inhibitors
DescriptionGlioblastoma multiforme (GBM) is a highly lethal brain tumor. Due to resistance to current therapies, patient prognosis remains poor and development of novel and effective GBM therapy is crucial. Glioma stem cells (GSCs) have gained attention as therapeutic target in GBM due to their relative resistance to current therapies and potent tumor-initiating ability. Recent studies including our own identified that the mitotic kinase, maternal embryonic leucine-zipper kinase (MELK), is highly expressed in GBM tissues, specifically in GSCs, and its expression is inversely correlated with the post-surgical survival period of GBM patients. In addition, patient-derived GSCs depend on MELK for their survival and growth both in vitro and in vivo. Here, we provide evidence that the kinase activity of MELK is essential for the action of MELK in GSCs and vital for GBM growth. We utilized in silico structure-based analysis for protein-compound interaction to predict that a recently identified small molecule, Compound 1 (C1), binds to the kinase-active site of MELK protein and eliminates MELK kinase activity in nanomolar concentrations. When treated with C1, GSCs undergo mitotic arrest and subsequent cellular apoptosis in vitro, a phenotype identical to that observed using MELK shRNA-mediated knockdown. C1 treatment strongly induces tumor cell apoptosis in slice cultures of GBM surgical specimens and attenuates growth of mouse intracranial tumors derived from GSCs in a dose-dependent manner. Lastly, C1 treatment sensitizes GSCs to radiation treatment. Collectively, these data indicate that targeting MELK kinase activity is a promising approach to attenuate GBM growth by eliminating GSCs in tumors.
Landing Pagehttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE50227
RepositoryGene Expression Omnibus
Tools used to analyze the dataset
Keyword
Dataset Accession
Enrichr
Published May 2016
A comprehensive gene set enrichment analysis web server 2016 update
7759
65
Characteristic Direction
Published March 2014
A geometrical multivariate approach to identify differentially expressed genes
26829
GeneMANIA
Published June 2010
Biological network integration for gene prioritization and predicting gene function
7435
L1000CDS2
Published August 2016
An ultra-fast LINCS L1000 Characteristic Direction signature search engine
7756
PAEA
Published November 2015
Enrichment analysis tool implementing the principal angle method
3879
Canned Analyses generated with the dataset
Filters  
Dataset Accession
Tool Name
Direction
Geneset
Small molecules which mimic MELK druginhibition
L1000CDS2, Characteristic Direction
The L1000 database was queried in order to identify small molecule perturbations which mim...
Small molecules which reverse MELK druginhibition
L1000CDS2, Characteristic Direction
The L1000 database was queried in order to identify small molecule perturbations which rev...
Enrichment analysis of genes dysregulated in MELK druginhibition
PAEA, Characteristic Direction
An enrichment analysis was performed on the top most dyresgulated genes determined by appl...
Interaction network and enrichment analysis of genes downregulated in MELK druginhibition
GeneMANIA, Characteristic Direction
The analysis explores the gene interaction network and pathway enrichment of the top 50 mo...
Interaction network and enrichment analysis of genes upregulated in MELK druginhibition
GeneMANIA, Characteristic Direction
The analysis explores the gene interaction network and pathway enrichment of the top 50 mo...
Enrichment analysis of genes downregulated in MELK druginhibition
Enrichr, Characteristic Direction
An enrichment analysis was performed on the top 500 most downregulated genes identified by...
Enrichment analysis of genes upregulated in MELK druginhibition
Enrichr, Characteristic Direction
An enrichment analysis was performed on the top 500 most upregulated genes identified by a...
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