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MYC activity mitigates response to rapamycin in prostate cancer through eukaryotic initiation factor 4E-binding protein 1-mediated inhibition of autophagy.

ABSTRACT: Loss of PTEN and activation of phosphoinositide 3-kinase are commonly observed in advanced prostate cancer. Inhibition of mammalian target of rapamycin (mTOR), a downstream target of phosphoinositide 3-kinase signaling, results in cell cycle arrest and apoptosis in multiple in vitro and in vivo models of prostate cancer. However, single-agent use of mTOR inhibition has limited clinical success, and the identification of molecular events mitigating tumor response to mTOR inhibition remains a critical question. Here, using genetically engineered human prostate epithelial cells (PrEC), we show that MYC, a frequent target of genetic gain in prostate cancers, abrogates sensitivity to rapamycin by decreasing rapamycin-induced cytostasis and autophagy. Analysis of MYC and the mTOR pathway in human prostate tumors and PrEC showed selective increased expression of eukaryotic initiation factor 4E-binding protein 1 (4EBP1) with gain in MYC copy number or forced MYC expression, respectively. We have also found that MYC binds to regulatory regions of the 4EBP1 gene. Suppression of 4EBP1 expression resulted in resensitization of MYC-expressing PrEC to rapamycin and increased autophagy. Taken together, our findings suggest that MYC expression abrogates sensitivity to rapamycin through increased expression of 4EBP1 and reduced autophagy.

SUBMITTER: Balakumaran BS

PROVIDER: S-EPMC2756305 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Eukaryotic initiation factor 4E.

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Consideration of Binding Kinetics in the Design of Stapled Peptide Mimics of the Disordered Proteins Eukaryotic Translation Initiation Factor 4E-Binding Protein 1 and Eukaryotic Translation Initiation Factor 4G.

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Discovery and characterization of conserved binding of eIF4E 1 (CBE1), a eukaryotic translation initiation factor 4E-binding plant protein.

Project description:In many eukaryotes, translation initiation is regulated by proteins that bind to the mRNA cap-binding protein eukaryotic translation initiation factor 4E (eIF4E). These proteins commonly prevent association of eIF4E with eIF4G or form repressive messenger ribonucleoproteins that exclude the translation machinery. Such gene-regulatory mechanisms in plants, and even the presence of eIF4E-interacting proteins other than eIF4G (and the plant-specific isoform eIFiso4G, which binds eIFiso4E), are unknown. Here, we report the discovery of a plant-specific protein, conserved binding of eIF4E 1 (CBE1). We found that CBE1 has an evolutionarily conserved eIF4E-binding motif in its N-terminal domain and binds eIF4E or eIFiso4E in vitro CBE1 thereby forms cap-binding complexes and is an eIF4E-dependent constituent of these complexes in vivo Of note, plant mutants lacking CBE1 exhibited dysregulation of cell cycle-related transcripts and accumulated higher levels of mRNAs encoding proteins involved in mitosis than did WT plants. Our findings indicate that CBE1 is a plant protein that can form mRNA cap-binding complexes having the potential for regulating gene expression. Because mammalian translation factors are known regulators of cell cycle progression, we propose that CBE1 may represent such first translation factor-associated plant-specific cell cycle regulator.

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