Abstract
The mTOR pathway controls mRNA translation of mitogenic proteins and is a central regulator of metabolism in malignant cells. Development of malignant cell resistance is a limiting factor to the effects of mTOR inhibitors, but the mechanisms accounting for such resistance are not well understood. We provide evidence that mTORC1 inhibition by rapamycin results in engagement of a negative feedback regulatory loop in malignant medulloblastoma cells, involving phosphorylation of the eukaryotic translation-initiation factor eIF4E. This eIF4E phosphorylation is Mnk2- mediated, but Mnk1-independent, and acts as a survival mechanism for medulloblastoma cells. Pharmacological targeting of Mnk1/2 or siRNA-mediated knockdown of Mnk2 sensitizes medulloblastoma cells to mTOR inhibition and promotes suppression of malignant cell proliferation and anchorage-independent growth. Altogether, these findings provide evidence for the existence of a Mnk2-controlled feedback loop in medulloblastoma cells that accounts for resistance to mTOR inhibitors, and raise the potential for combination treatments of mTOR and Mnk inhibitors for the treatment of medulloblastoma.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Antibiotics, Antineoplastic / pharmacology*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Cerebellar Neoplasms / enzymology*
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Cerebellar Neoplasms / genetics
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Cerebellar Neoplasms / pathology
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Dose-Response Relationship, Drug
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Drug Resistance, Neoplasm
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Eukaryotic Initiation Factor-4E / genetics
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Eukaryotic Initiation Factor-4E / metabolism*
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Feedback, Physiological
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Mechanistic Target of Rapamycin Complex 1
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Medulloblastoma / enzymology*
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Medulloblastoma / genetics
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Medulloblastoma / pathology
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Multiprotein Complexes / antagonists & inhibitors*
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Multiprotein Complexes / metabolism
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Phosphorylation
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Protein Kinase Inhibitors / pharmacology*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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RNA Interference
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Signal Transduction / drug effects
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Sirolimus / pharmacology*
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TOR Serine-Threonine Kinases / antagonists & inhibitors*
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TOR Serine-Threonine Kinases / metabolism
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Transfection
Substances
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Antibiotics, Antineoplastic
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Eukaryotic Initiation Factor-4E
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Intracellular Signaling Peptides and Proteins
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Multiprotein Complexes
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Protein Kinase Inhibitors
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MKNK2 protein, human
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Mechanistic Target of Rapamycin Complex 1
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Protein Serine-Threonine Kinases
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TOR Serine-Threonine Kinases
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Sirolimus