title: MNK1 pathway activity maintains protein synthesis in rapalog-treated gliomas.
abstract: High levels of mammalian target of rapamycin complex 1 (mTORC1) activity in malignant gliomas promote tumor progression, suggesting that targeting mTORC1 has potential as a therapeutic strategy. Remarkably, clinical trials in patients with glioma revealed that rapamycin analogs (rapalogs) have limited efficacy, indicating activation of resistance mechanisms. Targeted depletion of MAPK-interacting Ser/Thr kinase 1 (MNK1) sensitizes glioma cells to the mTORC1 inhibitor rapamycin through an indistinct mechanism. Here, we analyzed how MNK1 and mTORC1 signaling pathways regulate the assembly of translation initiation complexes, using the cap analog m7GTP to enrich for initiation complexes in glioma cells followed by mass spectrometry-based quantitative proteomics. Association of eukaryotic translation initiation factor 4E (eIF4E) with eIF4E-binding protein 1 (4EBP1) was regulated by the mTORC1 pathway, whereas pharmacological blocking of MNK activity by CGP57380 or MNK1 knockdown, along with mTORC1 inhibition by RAD001, increased 4EBP1 binding to eIF4E. Furthermore, combined MNK1 and mTORC1 inhibition profoundly inhibited 4EBP1 phosphorylation at Ser65, protein synthesis and proliferation in glioma cells, and reduced tumor growth in an orthotopic glioblastoma (GBM) mouse model. Immunohistochemical analysis of GBM samples revealed increased 4EBP1 phosphorylation. Taken together, our data indicate that rapalog-activated MNK1 signaling promotes glioma growth through regulation of 4EBP1 and indicate a molecular cross-talk between the mTORC1 and MNK1 pathways that has potential to be exploited therapeutically.
authors.forename: Michal
authors.initials: M
authors.lastname: Grzmil
authors.forename: Roland M
authors.initials: RM
authors.lastname: Huber
authors.forename: Daniel
authors.initials: D
authors.lastname: Hess
authors.forename: Stephan
authors.initials: S
authors.lastname: Frank
authors.forename: Debby
authors.initials: D
authors.lastname: Hynx
authors.forename: Gerald
authors.initials: G
authors.lastname: Moncayo
authors.forename: Dominique
authors.initials: D
authors.lastname: Klein
authors.forename: Adrian
authors.initials: A
authors.lastname: Merlo
authors.forename: Brian A
authors.initials: BA
authors.lastname: Hemmings
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D046912:Multiprotein Complexes / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011485:Protein Binding; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011687:Purines / Q000737:chemistry; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000814:Aniline Compounds; C466997:CGP 57380; D039561:Eukaryotic Initiation Factor-4E; D046912:Multiprotein Complexes; D011687:Purines; C106281:Mknk1 protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus