TY - JOUR
T1 - A MYC–GCN2–eIF2α negative feedback loop limits protein synthesis to prevent MYC-dependent apoptosis in colorectal cancer
AU - Schmidt, Stefanie
AU - Gay, David
AU - Uthe, Friedrich Wilhelm
AU - Denk, Sarah
AU - Paauwe, Madelon
AU - Matthes, Niels
AU - Diefenbacher, Markus Elmar
AU - Bryson, Sheila
AU - Warrander, Fiona Clare
AU - Erhard, Florian
AU - Ade, Carsten Patrick
AU - Baluapuri, Apoorva
AU - Walz, Susanne
AU - Jackstadt, Rene
AU - Ford, Catriona
AU - Vlachogiannis, Georgios
AU - Valeri, Nicola
AU - Otto, Christoph
AU - Schülein-Völk, Christina
AU - Maurus, Katja
AU - Schmitz, Werner
AU - Knight, John Raymond Philip
AU - Wolf, Elmar
AU - Strathdee, Douglas
AU - Schulze, Almut
AU - Germer, Christoph Thomas
AU - Rosenwald, Andreas
AU - Sansom, Owen James
AU - Eilers, Martin
AU - Wiegering, Armin
N1 - Funding Information:
This study was supported by grants from the following sources: 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.); 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 programme of the German Cancer Aid (Deutsche Krebshilfe). Additional personal financial support was given by S. Kratz. The technical expertise of S. Roth, B. Bauer, H. Marouf and C. Schneider is gratefully acknowledged. The invaluable support of the Histology Service, the Biological Services Unit and all the core services at the Cancer Research UK Beatson Institute is greatly appreciated (Cancer Research UK core grant C596/A17196).
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85075052323&partnerID=8YFLogxK
U2 - 10.1038/s41556-019-0408-0
DO - 10.1038/s41556-019-0408-0
M3 - Article
C2 - 31685988
AN - SCOPUS:85075052323
SN - 1465-7392
VL - 21
SP - 1413
EP - 1424
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 11
ER -
