Back to Search
Start Over
A MYC-GCN2-eIF2α negative feedback loop limits protein synthesis to prevent MYC-dependent apoptosis in colorectal cancer.
- 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.
- Subjects :
- Adenomatous Polyposis Coli Protein genetics
Adenomatous Polyposis Coli Protein metabolism
Animals
Apoptosis genetics
Cell Line, Tumor
Cell Movement
Cell Proliferation
Colon metabolism
Colon pathology
Colorectal Neoplasms metabolism
Colorectal Neoplasms mortality
Colorectal Neoplasms pathology
Eukaryotic Initiation Factor-2 metabolism
Eukaryotic Initiation Factor-2B antagonists & inhibitors
Eukaryotic Initiation Factor-2B genetics
Eukaryotic Initiation Factor-2B metabolism
Feedback, Physiological
Female
HCT116 Cells
HEK293 Cells
Humans
Male
Mice
Mice, Inbred C57BL
Protein Biosynthesis
Protein Serine-Threonine Kinases metabolism
Proto-Oncogene Proteins c-myc metabolism
Signal Transduction
Survival Analysis
Xenograft Model Antitumor Assays
Colorectal Neoplasms genetics
Eukaryotic Initiation Factor-2 genetics
Gene Expression Regulation, Neoplastic
Protein Serine-Threonine Kinases genetics
Proto-Oncogene Proteins c-myc genetics
Subjects
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