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

AI Article Synopsis

  • Tumors rely on altered protein synthesis for their growth, pointing to the potential for targeting mRNA translation mechanisms in cancer therapy.* -
  • The loss of the APC gene in colorectal tumors increases reliance on the translation initiation factor eIF2B5, where depleting eIF2B5 triggers a stress response and leads to cell death by affecting MYC levels.* -
  • High MYC levels in APC-deficient cells activate specific kinases, and inhibiting these kinases shows similar effects to depleting eIF2B5, highlighting a feedback loop that could be targeted for colorectal cancer treatment.*

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927814PMC
http://dx.doi.org/10.1038/s41556-019-0408-0DOI Listing

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