Abstract
Glioblastoma 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 a therapeutic target in GBM due to their relative resistance to current therapies and potent tumor-initiating ability. Previously, we 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 demonstrate evidence that the role of MELK in the GSC survival is specifically dependent on its kinase activity. With in silico structure-based analysis for protein-compound interaction, we identified the small molecule Compound 1 (C1) is predicted to bind to the kinase-active site of MELK protein. Elimination of MELK kinase activity was confirmed by in vitro kinase assay in nano-molar concentrations. When patient-derived GSCs were treated with C1, they underwent mitotic arrest and subsequent cellular apoptosis in vitro, a phenotype identical to that observed with shRNA-mediated MELK knockdown. In addition, C1 treatment strongly induced tumor cell apoptosis in slice cultures of GBM surgical specimens and attenuated 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.
Highlights
Glioblastoma multiforme (GBM) is the most common and lethal primary brain tumor in adults, and there is an urgent need to develop novel therapeutic strategies that effectively target therapy-resistant GBM cells
We demonstrated that Maternal embryonic leucine zipper kinase (MELK) acts on glioma stem cells (GSCs) survival through its kinase activity
We found that Compound 1 (C1) treatment sensitizes GSCs to radiation-induced cell death, supporting C1 as an attractive molecule-targeting therapy to combine with current standard protocols of GBM treatment
Summary
Glioblastoma multiforme (GBM) is the most common and lethal primary brain tumor in adults, and there is an urgent need to develop novel therapeutic strategies that effectively target therapy-resistant GBM cells. To gain insights in the mechanisms of action, we recently identified that MELK forms a protein complex with the oncogenic transcription factors c-JUN and FOXM1 in GSCs but not in non-GSCs or normal stem/progenitor cells [18,19]. Both of these protein interactions are dependent on the MELK kinase domain [18]. These results suggest that inhibition of the kinase activity of MELK could disrupt key interactions with pivotal oncogenes in cancer cells, while relatively sparing normal cells. We sought to identify a novel small molecule that potently inhibits MELK kinase activity
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