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

Authors :
Schmidt S
Gay D
Uthe FW
Denk S
Paauwe M
Matthes N
Diefenbacher ME
Bryson S
Warrander FC
Erhard F
Ade CP
Baluapuri A
Walz S
Jackstadt R
Ford C
Vlachogiannis G
Valeri N
Otto C
Schülein-Völk C
Maurus K
Schmitz W
Knight JRP
Wolf E
Strathdee D
Schulze A
Germer CT
Rosenwald A
Sansom OJ
Eilers M
Wiegering A
Source :
Nature cell biology [Nat Cell Biol] 2019 Nov; Vol. 21 (11), pp. 1413-1424. Date of Electronic Publication: 2019 Nov 04.
Publication Year :
2019

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.

Details

Language :
English
ISSN :
1476-4679
Volume :
21
Issue :
11
Database :
MEDLINE
Journal :
Nature cell biology
Publication Type :
Academic Journal
Accession number :
31685988
Full Text :
https://doi.org/10.1038/s41556-019-0408-0