Abstract
Activation of eIF4B correlates with Abl-mediated cellular transformation, but the precise mechanisms are largely unknown. Here we show that eIF4B is a convergent substrate of JAK/STAT/Pim and PI3K/Akt/mTOR pathways in Abl transformants. Both pathways phosphorylated eIF4B in Abl-transformed cells, and such redundant regulation was responsible for the limited effect of single inhibitor on Abl oncogenicity. Persistent inhibition of one signaling pathway induced the activation of the other pathway and thereby restored the phosphorylation levels of eIF4B. Simultaneous inhibition of the two pathways impaired eIF4B phosphorylation more effectively, and synergistically induced apoptosis in Abl transformed cells and inhibited the growth of engrafted tumors in nude mice. Similarly, the survival of Abl transformants exhibited a higher sensitivity to the pharmacological inhibition, when combined with the shRNA-based silence of the other pathway. Interestingly, such synergy was dependent on the phosphorylation status of eIF4B on Ser422, as overexpression of eIF4B phosphomimetic mutant S422E in the transformants greatly attenuated the synergistic effects of these inhibitors on Abl oncogenicity. In contrast, eIF4B knockdown sensitized Abl transformants to undergo apoptosis induced by the combined blockage. Collectively, the results indicate that eIF4B integrates the signals from Pim and PI3K/Akt/mTOR pathways in Abl-expressing leukemic cells, and is a promising therapeutic target for such cancers.
Keywords:
AKT; Abl oncogene; Pim kinase; eIF4B; tumorigenesis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibiotics, Antineoplastic / pharmacology
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Blotting, Western
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Cell Line
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Cell Survival / drug effects
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Cell Survival / genetics
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism
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Enzyme Inhibitors / pharmacology
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Eukaryotic Initiation Factors / genetics
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Eukaryotic Initiation Factors / metabolism*
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HEK293 Cells
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Humans
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K562 Cells
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Leukemia, Experimental / drug therapy
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Leukemia, Experimental / genetics
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Leukemia, Experimental / metabolism
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Mice, Inbred BALB C
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Mice, Nude
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation / drug effects
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Proto-Oncogene Proteins c-abl / genetics
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Proto-Oncogene Proteins c-abl / metabolism*
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism*
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Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors
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Proto-Oncogene Proteins c-pim-1 / genetics
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Proto-Oncogene Proteins c-pim-1 / metabolism*
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RNA Interference
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Sirolimus / pharmacology
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism*
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Tumor Burden / drug effects
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Xenograft Model Antitumor Assays
Substances
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Antibiotics, Antineoplastic
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Enzyme Inhibitors
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Eukaryotic Initiation Factors
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Phosphoinositide-3 Kinase Inhibitors
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eIF-4B
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Proto-Oncogene Proteins c-abl
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-pim-1
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TOR Serine-Threonine Kinases
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Sirolimus