AI Article Synopsis
- The process of translation, which is energy-intensive, is regulated by the mTOR signaling pathway, particularly affecting the eIF4F complex, and disrupting mTOR can lead to cancer and influence chemotherapy effectiveness.
- The study presents a new RNAi approach alongside pharmacological methods to explore the role of eIF4F in tumors initiated by Myc, discovering that high Myc levels correlate with unregulated eIF4F activity in early lymphoma development.
- Inhibition of eIF4F proves to be particularly lethal for Myc-overexpressing pre-malignant cells, slowing down tumor formation, while its suppression in normal regenerating cells is tolerated and reversible, making eIF4F a promising target for cancer treatment.
Article 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3346676 | PMC |
| http://dx.doi.org/10.1016/j.celrep.2012.02.010 | DOI Listing |
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