2. Academic Validation
  3. eIF4E S209 phosphorylation licenses myc- and stress-driven oncogenesis

eIF4E S209 phosphorylation licenses myc- and stress-driven oncogenesis

  • Elife. 2020 Nov 2;9:e60151. doi: 10.7554/eLife.60151.
Hang Ruan  # 1 2,  Xiangyun Li  # 1 2 3,  Xiang Xu 3 4,  Brian J Leibowitz 1 2,  Jingshan Tong 2 5,  Lujia Chen 2 6,  Luoquan Ao 3 4,  Wei Xing 3 4,  Jianhua Luo 1,  Yanping Yu 1,  Robert E Schoen 7,  Nahum Sonenberg 8,  Xinghua Lu 2 6,  Lin Zhang 2 5,  Jian Yu 1 2
Affiliations

Affiliations

  • 1 Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, United States.
  • 2 UPMC Hillman Cancer Center, Pittsburgh, United States.
  • 3 Department of Stem cell and regenerative medicine, Daping Hospital, Army Medical University, Chongqing, China.
  • 4 Central laboratory, State key laboratory of trauma, burn and combined Injury, Daping Hospital, Chongqing, China.
  • 5 Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States.
  • 6 Department of Biomedical informatics, University of Pittsburgh School of Medicine, Pittsburgh, United States.
  • 7 Departments of Medicine and Epidemiology, University of Pittsburgh, Pittsburgh, United States.
  • 8 Department of Biochemistry, Goodman Cancer Research Centre, McGill University, Montreal, Canada.
  • # Contributed equally.
PMID: 33135632 DOI: 10.7554/eLife.60151
Abstract

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 impact on total eIF4E levels, cap binding or global translation, but 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.

Keywords

KRAS; Myc; cancer biology; colon cancer; eIF4E S209; glutamine; human; mouse; the integrated stress response.

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