Targeting synthetic lethal interactions between Myc and the eIF4F complex impedes tumorigenesis.

Abstract

The energetically demanding process of translation is linked to multiple signaling events through mTOR-mediated regulation of eukaryotic initiation factor (eIF)4F complex assembly. Disrupting mTOR constraints on eIF4F activity can be oncogenic and alter chemotherapy response, making eIF4F an attractive antineoplastic target. Here, we combine a newly developed inducible RNAi platform and pharmacological targeting of eIF4F activity to define a critical role for endogenous eIF4F in Myc-dependent tumor initiation. We find elevated Myc levels are associated with deregulated eIF4F activity in the prelymphomatous stage of the Eμ-Myc lymphoma model. Inhibition of eIF4F is synthetic lethal with elevated Myc in premalignant pre-B/B cells resulting in reduced numbers of cycling pre-B/B cells and delayed tumor onset. At the organismal level, eIF4F suppression affected a subset of normal regenerating cells, but this was well tolerated and rapidly and completely reversible. Therefore, eIF4F is a key Myc client that represents a tumor-specific vulnerability.

• Authors: Chen-Ju Lin, Zeina Nasr, Prem K Premsrirut, John A Porco Jr, Yoshitaka Hippo, Scott W Lowe, Jerry Pelletier
• Journal: Cell reports (Cell Rep) Vol. 1 Issue 4 Pg. 325-33 (Apr 19 2012) ISSN: 2211-1247 [Electronic] United States
• PMID: 22573234 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Eukaryotic Initiation Factor-4F
• Myeloid Cell Leukemia Sequence 1 Protein
• Proto-Oncogene Proteins c-bcl-2
• Proto-Oncogene Proteins c-myc
• Triterpenes
• silvestrol
• Cyclin D1

Topics

• Animals
• Apoptosis (genetics)
• Cell Division (genetics)
• Cell Transformation, Neoplastic (drug effects, genetics)
• Cyclin D1 (metabolism)
• Enzyme Inhibitors (pharmacology)
• Eukaryotic Initiation Factor-4F (drug effects, metabolism, physiology)
• Mice
• Mice, Transgenic
• Myeloid Cell Leukemia Sequence 1 Protein
• Protein Biosynthesis (drug effects)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Proto-Oncogene Proteins c-myc (genetics, metabolism, physiology)
• RNA Interference
• Triterpenes (pharmacology)