Abstract
Abstract Glioblastoma multiform (GBM) is the most common and aggressive brain tumor entity, with a median survival of approximately one year. In the last decade, genetic profiling of brain tumors has improved our understanding of gliomagenesis and proposed many targeted therapies based on molecular interference with deregulated signaling networks. In a search for novel molecular targets, our kinome-focused microarray analysis identified overexpressed MAP kinase-interacting kinase 1 (MNK1) in primary GBM and its elevated protein level was confirmed in primary GBMs and in glioma cell lines. MNKs can bind to translation initiation factor eIF4G and phosphorylate the cap-binding protein eIF4E at Ser209 that is required for its oncogenic activity. Targeting MNK1 activity in GBM cells suppressed eIF4E phosphorylation, reduced proliferation and colony formation whereas, concomitant treatment with Mnk inhibitor CGP57380 and mTOR inhibitor rapamycin resulted in an additive effect on growth inhibition and cell cycle arrest. Analysis of polysomal profiles revealed inhibition of translation in CGP57380 and rapamycin treated cells. Microarray analysis of total and polysomal RNA from MNK1-depleted GBM cells identified mRNAs involved in regulation of TGF-β pathway. The translation of SMAD2 mRNA as well as TGF-β-induced cell motility was regulated by MNK1-signaling. TGF-β pathways regulate growth of glioma-initiating cells that are involved in tumorigenesis, resistance to cancer therapies and relapse. Our most recent analysis identified high activity of MNK1 pathway in human GBM-derived spheres. Furthermore, inhibition of MNK1 activity significantly reduced formation and growth of cancer spheres. Our model of gliomasphere growth regulation via MNK1-signaling pathways together with clinical implications will be presented and discussed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-169. doi:10.1158/1538-7445.AM2011-LB-169
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