MNK kinases facilitate c-myc IRES activity in rapamycin-treated multiple myeloma cells

Oncogene. 2013 Jan 10;32(2):190-7. doi: 10.1038/onc.2012.43. Epub 2012 Feb 27.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 5' Untranslated Regions*
  • Aniline Compounds / pharmacology
  • Animals
  • Butadienes / pharmacology
  • Cell Line, Tumor
  • Enzyme Inhibitors / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Fibroblasts / metabolism
  • Genes, myc*
  • Humans
  • Imidazoles / pharmacology
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Multiple Myeloma / genetics*
  • Multiple Myeloma / metabolism*
  • Nitriles / pharmacology
  • Phosphorylation
  • Protein Biosynthesis
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Purines / pharmacology
  • Pyridines / pharmacology
  • RNA Interference
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering
  • Sirolimus / pharmacology*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism*
  • Up-Regulation
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors

Substances

  • 5' Untranslated Regions
  • Aniline Compounds
  • Butadienes
  • CGP 57380
  • Enzyme Inhibitors
  • Imidazoles
  • Intracellular Signaling Peptides and Proteins
  • MYC protein, human
  • Nitriles
  • Proto-Oncogene Proteins c-myc
  • Purines
  • Pyridines
  • RNA, Messenger
  • RNA, Small Interfering
  • U 0126
  • MKNK1 protein, human
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • MKNK2 protein, human
  • Protein-Serine-Threonine Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases
  • SB 203580
  • Sirolimus