A MYC/GCN2/eIF2α negative feedback loop limits protein synthesis to prevent MYC-dependent apoptosis in colorectal cancer

Schmidt, S. et al. (2019) A MYC/GCN2/eIF2α negative feedback loop limits protein synthesis to prevent MYC-dependent apoptosis in colorectal cancer. Nature Cell Biology, 21, pp. 1413-1424. (doi: 10.1038/s41556-019-0408-0) (PMID:31685988) (PMCID:PMC6927814)

Abstract

Tumours depend on altered rates of protein synthesis for growth and survival, which suggests that mechanisms controlling mRNA translation may be exploitable for therapy. Here, we show that loss of APC, which occurs almost universally in colorectal tumours, strongly enhances the dependence on the translation initiation factor eIF2B5. Depletion of eIF2B5 induces an integrated stress response and enhances translation of MYC via an internal ribosomal entry site. This perturbs cellular amino acid and nucleotide pools, strains energy resources and causes MYC-dependent apoptosis. eIF2B5 limits MYC expression and prevents apoptosis in APC-deficient murine and patient-derived organoids and in APC-deficient murine intestinal epithelia in vivo. Conversely, the high MYC levels present in APC-deficient cells induce phosphorylation of eIF2α via the kinases GCN2 and PKR. Pharmacological inhibition of GCN2 phenocopies eIF2B5 depletion and has therapeutic efficacy in tumour organoids, which demonstrates that a negative MYC–eIF2α feedback loop constitutes a targetable vulnerability of colorectal tumours.

• Item Type: Articles
• Additional Information: This study was supported by grants from the Else-Kröner-Fresenius Foundation (2015_A57 to A.W.), the interdisciplinary center for clinical research of the Medical Faculty Würzburg (IZKF B-186 and B-335 to A.W.), European Research Council Grants “AuroMYC” (Advanced Grant to M.E.) and "ColonCan" (Starting Grant to O.J.S; 311301), a Cancer Research UK Grand Challenge grant (A25045 to O.J.S.), Cancer Research UK core funding (A17196 and A21139 to O.J.S) and the Deutsche Forschungsgemeinschaft (DFG) (WO 2108/1-1 to E.W., FOR2314 and KFO DFG EI 222/8-1 grants to M.E., FOR2314 and KFO DFG WI 5037/2-2 to A.W.) and the Wilhelm Sander-Stiftung (to M.E). S.W. is supported by the Comprehensive Cancer Center program of the German Cancer Aid (Deutsche Krebshilfe).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Strathdee, Mr Douglas and Sansom, Professor Owen
• Authors: Schmidt, S., Gay, D., Uthe, F. W., Denk, S., Paauwe, M., Matthes, N., Diefenbacher, M. E., Bryson, S., Warrender, F. C., Erhard, F., Ade, C. P., Baluapuri, A., Walz, S., Jackstadt, R., Ford, C., Vlachogiannis, G., Valeri, N., Otto, C., Schulein-Volk, C., Maurus, K., Schmitz, W., Knight, J. R. P., Wolf, E., Strathdee, D., Schluze, A., Germer, C.-T., Rosenwald, A., Sansom, O. J., Eilers, M., and Wiegering, A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Cell Biology
• Publisher: Nature Research
• ISSN: 1465-7392
• ISSN (Online): 1476-4679
• Published Online: 04 November 2019
• Copyright Holders: Copyright © 2019 Springer Nature Limited
• First Published: First published in Nature Cell Biology 21:1413–1424
• Publisher Policy: Reproduced in accordance with the publisher copyright policy