To better understand a role of eIF4E S209 in oncogenic translation, we generated EIF4ES209A/+ heterozygous knockin (4EKI) HCT 116 human colorectal cancer (CRC) cells. 4EKI had little on total eIF4E levels, cap binding or global translation, while markedly reduced HCT 116 cell growth in spheroids and mice, and CRC organoid growth. 4EKI strongly inhibited Myc and ATF4 translation, the integrated Stress Response (ISR)-dependent glutamine metabolic signature, AKT activation and proliferation in vivo. 4EKI inhibited polyposis in ApcMin/+ mice by suppressing Myc protein and AKT activation. Furthermore, p-eIF4E was highly elevated in CRC precursor lesions in mouse and human. p-eIF4E cooperated with mutant KRAS to promote Myc and ISR-dependent glutamine addiction in various CRC cell lines, characterized by increased cell death, transcriptomic heterogeneity and immune suppression upon deprivation. These findings demonstrate a critical role of eIF4E S209-dependent translation in Myc and stress-driven oncogenesis and as a potential therapeutic vulnerability.
Microarray data is deposited in Dryad under doi:10.5061/dryad.tb2rbnzxm.All data generated or analyzed during this study are included in the manuscript and supporting files.
Microarray dataDryad Digital Repository, doi:10.5061/dryad.tb2rbnzxm.
- Jian Yu
- Lin Zhang
- Lin Zhang
- Lin Zhang
- Xinghua Lu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (# 19085635 and 18063020) of the University of Pittsburgh. All animal experiments were approved by the University of Pittsburgh Institutional Animal Care and Use Committee under Animal welfare assurance number A-3187-01. No surgery or invasive procedure was performed and every effort was made to minimize suffering with humane sacrifice.
- Wafik S El-Deiry, Brown University, United States
© 2020, Ruan et al.
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