A MYC-GCN2-eIF2[alpha] negative feedback loop limits protein synthesis to prevent MYC-dependent apoptosis in colorectal cancer

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 tra...

Full description

Saved in:
Bibliographic Details
Published inNature cell biology Vol. 21; no. 11; pp. 1413 - 1424
Main Authors Schmidt, Stefanie, Gay, David, Uthe, Friedrich Wilhelm, Denk, Sarah, Paauwe, Madelon, Matthes, Niels, Diefenbacher, Markus Elmar
Format Journal Article
LanguageEnglish
Published Nature Publishing Group 01.11.2019
Subjects
Apoptosis
Colorectal cancer
Genetic translation
Prevention
Protein biosynthesis
RNA
Scientific equipment and supplies industry
United States
United Kingdom
Online AccessGet full text

Cover

More Information
Summary: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 eIF2[alpha] 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-eIF2[alpha] feedback loop constitutes a targetable vulnerability of colorectal tumours.
ISSN:1465-7392
1476-4679
DOI:10.1038/s41556-019-0408-0