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Targeting Translation Initiation Bypasses Signaling Crosstalk Mechanisms That Maintain High MYC Levels in Colorectal Cancer
- Source :
- Cancer Discovery. 5:768-781
- Publication Year :
- 2015
- Publisher :
- American Association for Cancer Research (AACR), 2015.
-
Abstract
- Deregulated expression of MYC is a driver of colorectal carcinogenesis, suggesting that inhibiting MYC may have significant therapeutic value. The PI3K and mTOR pathways control MYC turnover and translation, respectively, providing a rationale to target both pathways to inhibit MYC. Surprisingly, inhibition of PI3K does not promote MYC turnover in colon carcinoma cells, but enhances MYC expression because it promotes FOXO-dependent expression of growth factor receptors and MAPK-dependent transcription of MYC. Inhibition of mTOR fails to inhibit translation of MYC, because levels of 4EBPs are insufficient to fully sequester eIF4E and because an internal ribosomal entry site element in the 5′-untranslated region of the MYC mRNA permits translation independent of eIF4E. A small-molecule inhibitor of the translation factor eIF4A, silvestrol, bypasses the signaling feedbacks, reduces MYC translation, and inhibits tumor growth in a mouse model of colorectal tumorigenesis. We propose that targeting translation initiation is a promising strategy to limit MYC expression in colorectal tumors. Significance: Inhibiting MYC function is likely to have a significant therapeutic impact in colorectal cancers. Here, we explore several strategies to target translation initiation in order to block MYC expression. We show that a small-molecule inhibitor of eIF4A inhibits MYC expression and suppresses tumor growth in vivo. Cancer Discov; 5(7); 768–81. ©2015 AACR. See related commentary by Castell and Larsson, p. 701. This article is highlighted in the In This Issue feature, p. 681
- Subjects :
- Colorectal cancer
Antineoplastic Agents
Biology
Proto-Oncogene Proteins c-myc
Mice
Eukaryotic translation
Downregulation and upregulation
Growth factor receptor
Cell Line, Tumor
medicine
Animals
Humans
Translation factor
Peptide Chain Initiation, Translational
PI3K/AKT/mTOR pathway
Cell Proliferation
EIF4E
HCT116 Cells
medicine.disease
Xenograft Model Antitumor Assays
Molecular biology
Triterpenes
Up-Regulation
Eukaryotic Initiation Factor-4E
Oncology
eIF4A
Cancer research
Caco-2 Cells
Colorectal Neoplasms
HeLa Cells
Signal Transduction
Subjects
Details
- ISSN :
- 21598290 and 21598274
- Volume :
- 5
- Database :
- OpenAIRE
- Journal :
- Cancer Discovery
- Accession number :
- edsair.doi.dedup.....fe074971636af5e50c8f857d606e0ff6