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

Nat Cell Biol. 2019 Nov;21(11):1413-1424. doi: 10.1038/s41556-019-0408-0. Epub 2019 Nov 4.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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 / genetics*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / mortality
  • Colorectal Neoplasms / pathology
  • Eukaryotic Initiation Factor-2 / genetics*
  • Eukaryotic Initiation Factor-2 / metabolism
  • Eukaryotic Initiation Factor-2B / antagonists & inhibitors
  • Eukaryotic Initiation Factor-2B / genetics
  • Eukaryotic Initiation Factor-2B / metabolism
  • Feedback, Physiological
  • Female
  • Gene Expression Regulation, Neoplastic*
  • HCT116 Cells
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Protein Biosynthesis
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-myc / genetics*
  • Proto-Oncogene Proteins c-myc / metabolism
  • Signal Transduction
  • Survival Analysis
  • Xenograft Model Antitumor Assays


  • APC protein, human
  • Adenomatous Polyposis Coli Protein
  • EIF2B5 protein, human
  • Eukaryotic Initiation Factor-2
  • Eukaryotic Initiation Factor-2B
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • EIF2AK4 protein, human
  • Protein Serine-Threonine Kinases