title: MNK kinases facilitate c-myc IRES activity in rapamycin-treated multiple myeloma cells.
abstract: When mTOR inhibitor rapalogs prevent cap-dependent translation of cell-cycle proteins like c-myc, continuing tumor cell growth depends on cap-independent translation, which is mediated by internal ribosome entry sites (IRESes) located in the 5'-UTR (untranslated region) of transcripts. To investigate if rapalog-induced activation of MNK kinases had a role in such IRES activity, we studied multiple myeloma (MM) cells. Rapamycin (RAP)-activated MNK1 kinase activity in MM cell lines and primary specimens by a mitogen-activated protein kinase-dependent mechanism. Pharmacological inhibition of MNK activity or genetic silencing of MNK1 prevented a rapalog-induced upregulation of c-myc IRES activity. Although RAP, used alone, had little effect on myc protein expression, when combined with a MNK inhibitor, myc protein expression was abrogated. In contrast, there was no inhibition of myc RNA, consistent with an effect on myc translation. In a RAP-resistant MM cell lines as well as a resistant primary MM specimen, co-exposure to a MNK inhibitor or MNK1 knockdown significantly sensitized cells for RAP-induced cytoreduction. Studies in MNK-null murine embryonic fibroblasts additionally supported a role for MNK kinases in RAP-induced myc IRES stimulation. These results indicate that MNK kinase activity has a critical role in the fail-safe mechanism of IRES-dependent translation when mTOR is inhibited. As kinase activity also regulated sensitivity to RAP, the data also provide a rationale for therapeutically targeting MNK kinases for combined treatment with mTOR inhibitors.
authors.affiliation: Department of Medicine, Greater Los Angeles VA Healthcare Center and Jonsson Comprehensive Cancer Center of the UCLA Medical Center, Los Angeles, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Shi
authors.forename: P
authors.initials: P
authors.lastname: Frost
authors.forename: B
authors.initials: B
authors.lastname: Hoang
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.forename: R
authors.initials: R
authors.lastname: Fukunaga
authors.forename: J
authors.initials: J
authors.lastname: Gera
authors.forename: A
authors.initials: A
authors.lastname: Lichtenstein
mesh_terms: D020121:5' Untranslated Regions; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005347:Fibroblasts / Q000378:metabolism; D016259:Genes, myc; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D011687:Purines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D020121:5' Untranslated Regions; D000814:Aniline Compounds; D002070:Butadienes; C466997:CGP 57380; D004791:Enzyme Inhibitors; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; C489427:MYC protein, human; D009570:Nitriles; D016271:Proto-Oncogene Proteins c-myc; D011687:Purines; D011725:Pyridines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C113580:U 0126; C491395:MKNK1 protein, human; C546842:MTOR protein, human; C486342:MKNK2 protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D020123:Sirolimus