Targeting translation initiation bypasses signaling crosstalk mechanisms that maintain high MYC levels in colorectal cancer

Wiegering, A. et al. (2015) Targeting translation initiation bypasses signaling crosstalk mechanisms that maintain high MYC levels in colorectal cancer. Cancer Discovery, 5(7), pp. 768-781. (doi: 10.1158/2159-8290.CD-14-1040) (PMID:25934076) (PMCID:PMC5166973)

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.

• Item Type: Articles
• Additional Information: This work was supported by a grant from the interdisciplinary center for clinical research (IZKF B-186) of the medical faculty of Würzburg (to A. Wiegering). O.J. Sansom holds an European Research Council investigator award (COLONCAN), and T. Jamieson and O.J. Sansom are funded by Cancer Research UK (C596/A17196).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Jamieson, Mr Thomas and Sansom, Professor Owen
• Authors: Wiegering, A., Uthe, F. W., Jamieson, T., Ruoss, Y., Huttenrauch, M., Kuspert, M., Pfann, C., Nixon, C., Herold, S., Walz, S., Taranets, L., Germer, C.-T., Rosenwald, A., Sansom, O. J., and Eilers, M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cancer Discovery
• Publisher: American Association for Cancer Research
• ISSN: 2159-8274
• ISSN (Online): 2159-8290
• Published Online: 01 May 2015