Abstract
Cap-dependent translation is a potential cancer-related target (oncotarget) due to its critical role in cancer initiation and progression. 4EGI-1, an inhibitor of eIF4E/eIF4G interaction, was discovered by screening chemical libraries of small molecules. 4EGI-1 inhibits cap-dependent translation initiation by impairing the assembly of the eIF4E/eIF4G complex, and therefore is a potential anti-cancer agent. Here, we report that 4EGI-1 also inhibits mTORC1 signaling independent of its inhibitory role on cap-dependent translation initiation. The inhibition of mTORC1 signaling by 4EGI-1 activates Akt due to both abrogation of the negative feedback loops from mTORC1 to PI3K and activation of mTORC2. We further validated that mTORC2 activity is required for 4EGI-1-mediated Akt activation. The activated Akt counteracted the anticancer effects of 4EGI-1. In support of this model, inhibition of Akt potentiates the antitumor activity of 4EGI-1 both in vitro and in a xenograft mouse model in vivo. Our results suggest that a combination of 4EGI-1and Akt inhibitor is a rational approach for the treatment of cancer.
Keywords:
4EBP1; 4EBP1, eIF4E-binding protein 1; 4EGI-1; AKT; ER stress, endoplasmic reticulum stress; PI3K, phosphatidylinositol 3-kinase; cap-dependent translation; eIF4E; eIF4E, eukaryotic translation initiation factor 4E; eIF4F complex; mTORC1; mTORC1, mammalian target of rapamycin complex 1; mTORC2; mTORC2 mammalian target of rapamycin complex 2; p70S6K, ribosomal p70 S6 kinase.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / antagonists & inhibitors
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Antineoplastic Agents / therapeutic use
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Antineoplastic Agents / toxicity*
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Breast Neoplasms / drug therapy
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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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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Drug Synergism
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Female
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Heterocyclic Compounds, 3-Ring / therapeutic use
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Heterocyclic Compounds, 3-Ring / toxicity*
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Humans
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Hydrazones / therapeutic use
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Hydrazones / toxicity*
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MCF-7 Cells
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Mechanistic Target of Rapamycin Complex 1
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Mechanistic Target of Rapamycin Complex 2
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Multiprotein Complexes / antagonists & inhibitors
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Multiprotein Complexes / genetics
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Multiprotein Complexes / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoproteins / antagonists & inhibitors
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Phosphorylation / drug effects
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Protein Biosynthesis / drug effects
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Small Interfering / metabolism
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Signal Transduction / drug effects
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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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Thiazoles / therapeutic use
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Thiazoles / toxicity*
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Transplantation, Heterologous
Substances
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4EGI-1 compound
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Adaptor Proteins, Signal Transducing
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Antineoplastic Agents
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Cell Cycle Proteins
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EIF4EBP1 protein, human
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Heterocyclic Compounds, 3-Ring
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Hydrazones
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MK 2206
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Multiprotein Complexes
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Phosphoproteins
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RNA, Small Interfering
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Thiazoles
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Mechanistic Target of Rapamycin Complex 1
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Mechanistic Target of Rapamycin Complex 2
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases