Abstract
The Ras/Raf/MAPK and PI3K/Akt/mTORC1 cascades are two most aberrantly regulated pathways in cancers. As MAPK-interacting kinases (Mnks) are part of the convergent node of these two pathways, and play a pivotal role in cellular transformation, targeting Mnks has emerged as a potential therapeutic strategy. Herein, a dual-specific Mnk1/2 inhibitor MNKI-57 and a potent Mnk2-specific inhibitor MNKI-4 were selected for a panel screen against 28 human cancer cell lines. The study reveals that MNKI-57 and MNKI-4 are most potent against leukemia cells KYO-1 (i.e. BC-CML) and KG-1 (i.e. AML). Interestingly, we found that sensitivity of selected leukemia cells to Mnk inhibitors is correlated with the level of phosphorylated 4E-BP1 at Thr70. The anti-proliferative effects of Mnk inhibitors are cytostatic in the sensitive KYO-1 cells, inducing significant G1 arrest via down-regulation of cyclin D1 expression. In KYO-1 cells where Akt is not constitutively active, Mnk inhibitors increase the sensitivity of cells to rapamycin, resulting in a more pronounced anti-proliferative activity. Remarkably, the synergistic anti-proliferative effects are associated with a marked de-phosphorylation of 4E-BP1 at Thr70. Collectively, these data highlight the importance of 4E-BP1 as a key integrator in the MAPK and mTORC1 cascades, and suggest that a combined pharmacologic inhibition of mTORC1 and Mnk kinases offers an innovative therapeutic opportunity in BC-CML.
Keywords:
Apoptosis; CGP57380; Cell cycle; Chronic myeloid leukemia; Mnk inhibitor; Rapamycin.
Crown Copyright © 2014. Published by Elsevier Ireland Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Apoptosis / drug effects
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Blast Crisis / genetics
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Blast Crisis / metabolism
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Blast Crisis / pathology
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Blotting, Western
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Cell Cycle Proteins
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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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Cyclin D1 / metabolism
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Drug Synergism
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Flow Cytometry
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G1 Phase Cell Cycle Checkpoints / drug effects*
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HCT116 Cells
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HT29 Cells
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Humans
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
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Intracellular Signaling Peptides and Proteins / metabolism
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K562 Cells
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MCF-7 Cells
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Mechanistic Target of Rapamycin Complex 1
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Molecular Structure
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Multiprotein Complexes / antagonists & inhibitors*
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Multiprotein Complexes / metabolism
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Phosphorylation / drug effects
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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TOR Serine-Threonine Kinases / antagonists & inhibitors*
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TOR Serine-Threonine Kinases / metabolism
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Threonine / genetics
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Threonine / metabolism
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U937 Cells
Substances
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Adaptor Proteins, Signal Transducing
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Cell Cycle Proteins
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EIF4EBP1 protein, human
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Enzyme Inhibitors
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Intracellular Signaling Peptides and Proteins
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Multiprotein Complexes
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Phosphoproteins
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Cyclin D1
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Threonine
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MKNK1 protein, human
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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