MAP kinase-interacting kinase 1 regulates SMAD2-dependent TGF-β signaling pathway in human glioblastoma

• Published in: Cancer research (Chicago, Ill.) Ill.), 2011-03, Vol.71 (6), p.2392-2402
• Main Authors: Grzmil, Michal, Morin, Jr, Pier, Lino, Maria Maddalena, Merlo, Adrian, Frank, Stephan, Wang, Yuhua, Moncayo, Gerald, Hemmings, Brian A
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Aniline Compounds - pharmacology; Antibiotics, Antineoplastic - pharmacology; Blotting, Western; Cell Cycle - drug effects; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Drug Synergism; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Humans; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Male; Middle Aged; Oligonucleotide Array Sequence Analysis; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Purines - pharmacology; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Signal Transduction; Sirolimus - pharmacology; Smad2 Protein - genetics; Smad2 Protein - metabolism; Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta - pharmacology
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-10-3112

Glioblastoma multiforme (GBM) is the most common aggressive brain cancer with a median survival of approximately 1 year. In a search for novel molecular targets that could be therapeutically developed, our kinome-focused microarray analysis identified the MAP (mitogen-activated protein) kinase-interacting kinase 1 (MNK1) as an attractive theranostic candidate. MNK1 overexpression was confirmed in both primary GBMs and glioma cell lines. Inhibition of MNK1 activity in GBM cells by the small molecule CGP57380 suppressed eIF4E phosphorylation, proliferation, and colony formation whereas concomitant treatment with CGP57380 and the mTOR inhibitor rapamycin accentuated growth inhibition and cell-cycle arrest. siRNA-mediated knockdown of MNK1 expression reduced proliferation of cells incubated with rapamycin. Conversely, overexpression of full-length MNK1 reduced rapamycin-induced growth inhibition. 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. Translation of SMAD2 mRNA as well as TGF-β-induced cell motility and vimentin expression was regulated by MNK1 signaling. Tissue microarray analysis revealed a positive correlation between the immunohistochemical staining of MNK1 and SMAD2. Taken together, our findings offer insights into how MNK1 pathways control translation of cancer-related mRNAs including SMAD2, a key component of the TGF-β signaling pathway. Furthermore, they suggest MNK1-controlled translational pathways in targeted strategies to more effectively treat GBM.