MNK-eIF4E Signaling and mRNA Translation Regulate Mesenchymal Glioma Stem Cell Maintenance and Promote Therapeutic Resistance in Glioblastoma

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MAPK-interacting kinase (MNK) signaling leads to activation of cap-dependent mRNA translation through phosphorylation of the eukaryotic translation initiation factor 4E (eIF4E). In cancer cells, MNK-eIF4E signaling promotes translation of oncogenic mRNAs. In glioblastoma (GBM), the deadliest malignant brain tumor, MNK-eIF4E signaling is aberrantly activated and represents a promising therapeutic target. Here, we explored the role of MNK signaling in GBM and the tumor-initiating cells known as glioma stem cells (GSCs). We found that the MNKs and other genes involved in mRNA translation are enriched in mesenchymal subtype GBM patient samples and the corresponding GSC population. Using a novel MNK inhibitor, merestinib, we identified a role for MNK signaling and mRNA translation in patient-derived GSCs. Merestinib treatment inhibited cell viability, decreased colony formation, and activated apoptosis in GSCs. Furthermore, we found that merestinib depletes the cancer stem cell frequency in mesenchymal GSCs and prolongs survival in mice bearing intracranial GBM xenografts. In addition to these findings, we used high-throughput viability screens to identify the FDA-approved compound, arsenic trioxide (ATO), as a potent inhibitor of proneural, but not mesenchymal, GSCs. We found that ATO treatment leads to activation of MNK-eIF4E signaling in a negative-feedback manner, promoting therapeutic resistance. We also found that MNK1, but not MNK2, is responsible for phosphorylation of eIF4E in GBM cells treated with ATO. Using polysomal fractionation and microarray analysis, we identified an ATO-induced translatome, which is enriched for genes that negatively regulate apoptosis. We then found that MNK inhibition could sensitize mesenchymal GSCs to the pro-apoptotic effects of ATO. Finally, we analyzed outcomes in a phase I/II clinical trial of ATO for GBM patients. We found a correlation between better patient outcomes in the proneural subtype, when compared with other molecular subtypes. These findings suggest a role for MNK signaling in the maintenance of mesenchymal GSCs and support the development of strategies to disrupt MNK signaling in GBM to prevent tumor recurrence and overcome therapeutic resistance to ATO and other cytotoxic agents.

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  • 10/26/2018
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