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: Y Shi, P Frost, B Hoang, Y Yang, R Fukunaga, J Gera, A Lichtenstein
• Journal: Oncogene (Oncogene) Vol. 32 Issue 2 Pg. 190-7 (Jan 10 2013) ISSN: 1476-5594 [Electronic] England
• PMID: 22370634 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 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
• MKNK2 protein, human
• Protein Serine-Threonine Kinases
• TOR Serine-Threonine Kinases
• Extracellular Signal-Regulated MAP Kinases
• p38 Mitogen-Activated Protein Kinases
• SB 203580
• Sirolimus

Topics

• 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, genetics, metabolism)
• Mice
• Multiple Myeloma (genetics, metabolism)
• Nitriles (pharmacology)
• Phosphorylation
• Protein Biosynthesis
• Protein Serine-Threonine Kinases (antagonists & inhibitors, genetics, metabolism)
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• Purines (pharmacology)
• Pyridines (pharmacology)
• RNA Interference
• RNA, Messenger (genetics, metabolism)
• RNA, Small Interfering
• Sirolimus (pharmacology)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Up-Regulation
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors)