Targeting Translation Initiation Bypasses Signaling Crosstalk Mechanisms That Maintain High MYC Levels in Colorectal Cancer.
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.


CONCLUSIONS
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.
Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.|University Hospital Würzburg, Department of General, Visceral, Vascular and Pediatric Surgery, Würzburg, Germany.
Armin
A
Wiegering
Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
Friedrich W
FW
Uthe
CRUK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK.
Thomas
T
Jamieson
Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
Yvonne
Y
Ruoss
Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
Melanie
M
Hüttenrauch
Department of Biochemistry, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
Maritta
M
Küspert
Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
Christina
C
Pfann
CRUK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK.
Colin
C
Nixon
Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
Steffi
S
Herold
Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.|Comprehensive Cancer Center Mainfranken, University of Würzburg, Josef-Schneider-Str. 6, 97080 Würzburg, Germany.
Susanne
S
Walz
Comprehensive Cancer Center Mainfranken, University of Würzburg, Josef-Schneider-Str. 6, 97080 Würzburg, Germany.
Lyudmyla
L
Taranets
University Hospital Würzburg, Department of General, Visceral, Vascular and Pediatric Surgery, Würzburg, Germany.|Comprehensive Cancer Center Mainfranken, University of Würzburg, Josef-Schneider-Str. 6, 97080 Würzburg, Germany.
Christoph-Thomas
CT
Germer
Comprehensive Cancer Center Mainfranken, University of Würzburg, Josef-Schneider-Str. 6, 97080 Würzburg, Germany.|Institute of Pathology, University of Würzburg, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany.
Andreas
A
Rosenwald
CRUK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK.
Owen J
OJ
Sansom
Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.|Comprehensive Cancer Center Mainfranken, University of Würzburg, Josef-Schneider-Str. 6, 97080 Würzburg, Germany.
Martin
M
Eilers
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D039561:Eukaryotic Initiation Factor-4E / Q000037:antagonists & inhibitors; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D010442:Peptide Chain Initiation, Translational / Q000187:drug effects*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D014315:Triterpenes / Q000008:administration & dosage* / Q000494:pharmacology; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays; D001572:Benzofurans
D000970:Antineoplastic Agents; D039561:Eukaryotic Initiation Factor-4E; D016271:Proto-Oncogene Proteins c-myc; D014315:Triterpenes; C489427:MYC protein, human; C489897:silvestrol; D001572:Benzofurans