EIF4E S209 Phosphorylation Licenses Myc- and Stress-driven Oncogenesis

Overview

Journal Elife

Specialty Biology

Date 2020 Nov 2

PMID 33135632

Citations 17

Authors

Hang Ruan

Xiangyun Li

Xiang Xu

Brian J Leibowitz

Jingshan Tong

Lujia Chen

Luoquan Ao

Wei Xing

Jianhua Luo

Yanping Yu

Robert E Schoen

Nahum Sonenberg

Xinghua Lu

Lin Zhang

Jian Yu

Affiliations

Soon will be listed here.

Abstract

To better understand a role of eIF4E S209 in oncogenic translation, we generated 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 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 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.

Citing Articles

RNA-binding proteins as therapeutic targets in cancer.

Jungfleisch J, Gebauer F RNA Biol. 2025; 22(1):1-8.

PMID: 40016176 PMC: 11869776. DOI: 10.1080/15476286.2025.2470511.

PRSS23-eIF4E-c-Myc axis promotes gastric tumorigenesis and progression.

Zhou X, Guo Z, Pan Y, Yang S, Yan R Oncogene. 2025; .

PMID: 39920289 DOI: 10.1038/s41388-025-03294-3.

PPM1G dephosphorylates eIF4E in control of mRNA translation and cell proliferation.

Wang P, Li Z, Kim S, Xu H, Huang H, Yang C Life Sci Alliance. 2024; 7(10).

PMID: 39111820 PMC: 11306785. DOI: 10.26508/lsa.202402755.

GRP78 inhibitor YUM70 upregulates 4E-BP1 and suppresses c-MYC expression and viability of oncogenic c-MYC tumors.

Yamamoto V, Ha D, Liu Z, Huang M, Samanta S, Neamati N Neoplasia. 2024; 55:101020.

PMID: 38991376 PMC: 11294750. DOI: 10.1016/j.neo.2024.101020.

Molecular interaction and MD-simulations: investigation of Sizofiran as a promising anti-cancer agent targeting eIF4E in colorectal cancer.

Samykannu G, Mariyappan N, Natarajan J In Silico Pharmacol. 2024; 12(1):33.

PMID: 38655099 PMC: 11033251. DOI: 10.1007/s40203-024-00206-3.

References

Zhang L, Yu J . Role of apoptosis in colon cancer biology, therapy, and prevention. Curr Colorectal Cancer Rep. 2013; 9(4). PMC: 3836193. DOI: 10.1007/s11888-013-0188-z. View

Luo J, Solimini N, Elledge S . Principles of cancer therapy: oncogene and non-oncogene addiction. Cell. 2009; 136(5):823-37. PMC: 2894612. DOI: 10.1016/j.cell.2009.02.024. View

Appenzeller-Herzog C, Hall M . Bidirectional crosstalk between endoplasmic reticulum stress and mTOR signaling. Trends Cell Biol. 2012; 22(5):274-82. DOI: 10.1016/j.tcb.2012.02.006. View

Topisirovic I, Ruiz-Gutierrez M, Borden K . Phosphorylation of the eukaryotic translation initiation factor eIF4E contributes to its transformation and mRNA transport activities. Cancer Res. 2004; 64(23):8639-42. DOI: 10.1158/0008-5472.CAN-04-2677. View

Yu J, Yue W, Wu B, Zhang L . PUMA sensitizes lung cancer cells to chemotherapeutic agents and irradiation. Clin Cancer Res. 2006; 12(9):2928-36. DOI: 10.1158/1078-0432.CCR-05-2429. View

Cubillos-Ruiz J, Bettigole S, Glimcher L . Tumorigenic and Immunosuppressive Effects of Endoplasmic Reticulum Stress in Cancer. Cell. 2017; 168(4):692-706. PMC: 5333759. DOI: 10.1016/j.cell.2016.12.004. View

Ueda T, Sasaki M, Elia A, Chio I, Hamada K, Fukunaga R . Combined deficiency for MAP kinase-interacting kinase 1 and 2 (Mnk1 and Mnk2) delays tumor development. Proc Natl Acad Sci U S A. 2010; 107(32):13984-90. PMC: 2922567. DOI: 10.1073/pnas.1008136107. View

Baluapuri A, Wolf E, Eilers M . Target gene-independent functions of MYC oncoproteins. Nat Rev Mol Cell Biol. 2020; 21(5):255-267. PMC: 7611238. DOI: 10.1038/s41580-020-0215-2. View

Li X, Li M, Ruan H, Qiu W, Xu X, Zhang L . Co-targeting translation and proteasome rapidly kills colon cancer cells with mutant RAS/RAF via ER stress. Oncotarget. 2016; 8(6):9280-9292. PMC: 5354731. DOI: 10.18632/oncotarget.14063. View

10.

Robichaud N, Sonenberg N . Translational control and the cancer cell response to stress. Curr Opin Cell Biol. 2017; 45:102-109. DOI: 10.1016/j.ceb.2017.05.007. View

11.

Tameire F, Verginadis I, Koumenis C . Cell intrinsic and extrinsic activators of the unfolded protein response in cancer: Mechanisms and targets for therapy. Semin Cancer Biol. 2015; 33:3-15. PMC: 4523493. DOI: 10.1016/j.semcancer.2015.04.002. View

12.

Xu X, Vatsyayan J, Gao C, Bakkenist C, Hu J . Sumoylation of eIF4E activates mRNA translation. EMBO Rep. 2010; 11(4):299-304. PMC: 2854592. DOI: 10.1038/embor.2010.18. View

13.

Wang P, Zou F, Zhang X, Li H, Dulak A, Tomko Jr R . microRNA-21 negatively regulates Cdc25A and cell cycle progression in colon cancer cells. Cancer Res. 2009; 69(20):8157-65. PMC: 2763324. DOI: 10.1158/0008-5472.CAN-09-1996. View

14.

Zhang L, Zhou W, Velculescu V, Kern S, Hruban R, Hamilton S . Gene expression profiles in normal and cancer cells. Science. 1997; 276(5316):1268-72. DOI: 10.1126/science.276.5316.1268. View

15.

Dang C . A Time for MYC: Metabolism and Therapy. Cold Spring Harb Symp Quant Biol. 2017; 81:79-83. DOI: 10.1101/sqb.2016.81.031153. View

16.

Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A . ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics. 2009; 25(8):1091-3. PMC: 2666812. DOI: 10.1093/bioinformatics/btp101. View

17.

Yu J, Zhang L, Hwang P, Kinzler K, Vogelstein B . PUMA induces the rapid apoptosis of colorectal cancer cells. Mol Cell. 2001; 7(3):673-82. DOI: 10.1016/s1097-2765(01)00213-1. View

18.

Wang X, Flynn A, Waskiewicz A, Webb B, Vries R, Baines I . The phosphorylation of eukaryotic initiation factor eIF4E in response to phorbol esters, cell stresses, and cytokines is mediated by distinct MAP kinase pathways. J Biol Chem. 1998; 273(16):9373-7. DOI: 10.1074/jbc.273.16.9373. View

19.

Croft D, Mundo A, Haw R, Milacic M, Weiser J, Wu G . The Reactome pathway knowledgebase. Nucleic Acids Res. 2013; 42(Database issue):D472-7. PMC: 3965010. DOI: 10.1093/nar/gkt1102. View

20.

He K, Zheng X, Zhang L, Yu J . Hsp90 inhibitors promote p53-dependent apoptosis through PUMA and Bax. Mol Cancer Ther. 2013; 12(11):2559-68. PMC: 3823684. DOI: 10.1158/1535-7163.MCT-13-0284. View