Abstract
Targeting mTORC1 is a highly promising strategy in cancer therapy. Suppression of mTORC1 activity leads to rapid dephosphorylation of eIF4E-binding proteins (4E-BP1-3) and subsequent inhibition of mRNA translation. However, how the different 4E-BPs affect translation during prolonged use of mTOR inhibitors is not known. Here we show that the expression of 4E-BP3, but not that of 4E-BP1 or 4E-BP2, is transcriptionally induced during prolonged mTORC1 inhibition in vitro and in vivo. Mechanistically, our data reveal that 4E-BP3 expression is controlled by the transcription factor TFE3 through a cis-regulatory element in the EIF4EBP3 gene promoter. CRISPR/Cas9-mediated EIF4EBP3 gene disruption in human cancer cells mitigated the inhibition of translation and proliferation caused by prolonged treatment with mTOR inhibitors. Our findings show that 4E-BP3 is an important effector of mTORC1 and a robust predictive biomarker of therapeutic response to prolonged treatment with mTOR-targeting drugs in cancer.
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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Animals
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Antibiotics, Antineoplastic / pharmacology
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics*
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
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Breast Neoplasms / genetics*
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Breast Neoplasms / metabolism
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Breast Neoplasms / mortality
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Breast Neoplasms / pathology
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CRISPR-Cas Systems
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Carrier Proteins / genetics*
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Carrier Proteins / metabolism
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Cell Cycle Proteins
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Cell Proliferation
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Databases, Genetic
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Eukaryotic Initiation Factors / genetics
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Eukaryotic Initiation Factors / metabolism
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Female
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Gene Editing / methods
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Gene Expression Regulation, Neoplastic*
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HeLa Cells
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Hep G2 Cells
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Humans
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Indoles / pharmacology
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MCF-7 Cells
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Male
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Mice
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Mice, Inbred C57BL
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Protein Biosynthesis
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Purines / pharmacology
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Signal Transduction
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Sirolimus / pharmacology
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Survival Analysis
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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
Substances
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Adaptor Proteins, Signal Transducing
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Antibiotics, Antineoplastic
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Carrier Proteins
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Cell Cycle Proteins
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EIF4EBP1 protein, human
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EIF4EBP2 protein, human
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EIF4EBP3 protein, human
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Eukaryotic Initiation Factors
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Indoles
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Phosphoproteins
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Purines
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TFE3 protein, human
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MTOR protein, human
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TOR Serine-Threonine Kinases
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PP242
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Sirolimus