MNK Inhibition Disrupts Mesenchymal Glioma Stem Cells and Prolongs Survival in a Mouse Model of Glioblastoma
| Autor: | Ramana V. Davuluri, Ichiro Nakano, Ahmet Dirim Arslan, Yingtao Bi, Kristen Alley, Jessica Clymer, Jonathan B. Bell, Craig Horbinski, Stewart Goldman, Shi Yuan Cheng, Angel Alvarez, Hridi Hussain, Frank Eckerdt, Lisa P. Magnusson, Leonidas C. Platanias, C. David James |
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| Rok vydání: | 2016 |
| Předmět: |
Niacinamide
0301 basic medicine Cancer Research Indazoles Cell Survival Population Merestinib Antineoplastic Agents Protein Serine-Threonine Kinases Article Mice 03 medical and health sciences Cell Line Tumor Neurosphere Glioma medicine Animals Humans Phosphorylation education Molecular Biology Cell Proliferation education.field_of_study biology Brain Neoplasms Mesenchymal stem cell CD44 Intracellular Signaling Peptides and Proteins medicine.disease Survival Analysis Xenograft Model Antitumor Assays Hyaluronan Receptors 030104 developmental biology Oncology Cancer cell Neoplastic Stem Cells Cancer research biology.protein Neoplasm Grading Stem cell Glioblastoma |
| Zdroj: | Molecular Cancer Research. 14:984-993 |
| ISSN: | 1557-3125 1541-7786 |
| DOI: | 10.1158/1541-7786.mcr-16-0172 |
| Popis: | Glioblastoma multiforme remains the deadliest malignant brain tumor, with glioma stem cells (GSC) contributing to treatment resistance and tumor recurrence. We have identified MAPK-interacting kinases (MNK) as potential targets for the GSC population in glioblastoma multiforme. Isoform-level subtyping using The Cancer Genome Atlas revealed that both MNK genes (MKNK1 and MKNK2) are upregulated in mesenchymal glioblastoma multiforme as compared with other subtypes. Expression of MKNK1 is associated with increased glioma grade and correlated with the mesenchymal GSC marker, CD44, and coexpression of MKNK1 and CD44 predicts poor survival in glioblastoma multiforme. In established and patient-derived cell lines, pharmacologic MNK inhibition using LY2801653 (merestinib) inhibited phosphorylation of the eukaryotic translation initiation factor 4E, a crucial effector for MNK-induced mRNA translation in cancer cells and a marker of transformation. Importantly, merestinib inhibited growth of GSCs grown as neurospheres as determined by extreme limiting dilution analysis. When the effects of merestinib were assessed in vivo using an intracranial xenograft mouse model, improved overall survival was observed in merestinib-treated mice. Taken together, these data provide strong preclinical evidence that pharmacologic MNK inhibition targets mesenchymal glioblastoma multiforme and its GSC population. Implications: These findings raise the possibility of MNK inhibition as a viable therapeutic approach to target the mesenchymal subtype of glioblastoma multiforme. Mol Cancer Res; 14(10); 984–93. ©2016 AACR. |
| Databáze: | OpenAIRE |
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