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Review
. 2015 Jan 15;75(2):250-63.
doi: 10.1158/0008-5472.CAN-14-2789.

Targeting the eIF4F translation initiation complex: a critical nexus for cancer development

Jerry Pelletier  1 , Jeremy Graff  2 , Davide Ruggero  3 , Nahum Sonenberg  4
Affiliations
Review

Targeting the eIF4F translation initiation complex: a critical nexus for cancer development

Jerry Pelletier et al. Cancer Res. .

Abstract

Elevated protein synthesis is an important feature of many cancer cells and often arises as a consequence of increased signaling flux channeled to eukaryotic initiation factor 4F (eIF4F), the key regulator of the mRNA-ribosome recruitment phase of translation initiation. In many cellular and preclinical models of cancer, eIF4F deregulation results in changes in translational efficiency of specific mRNA classes. Importantly, many of these mRNAs code for proteins that potently regulate critical cellular processes, such as cell growth and proliferation, enhanced cell survival and cell migration that ultimately impinge on several hallmarks of cancer, including increased angiogenesis, deregulated growth control, enhanced cellular survival, epithelial-to-mesenchymal transition, invasion, and metastasis. By being positioned as the molecular nexus downstream of key oncogenic signaling pathways (e.g., Ras, PI3K/AKT/TOR, and MYC), eIF4F serves as a direct link between important steps in cancer development and translation initiation. Identification of mRNAs particularly responsive to elevated eIF4F activity that typifies tumorigenesis underscores the critical role of eIF4F in cancer and raises the exciting possibility of developing new-in-class small molecules targeting translation initiation as antineoplastic agents.

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Figures

Figure 1
Figure 1
Schematic model of cap-dependent binding of eIF4F-mRNA binding and subsequent destabilization of secondary structure. For clarity, the PABP-eIF4G interaction has not been recapitulated in this figure. Shown are four steps where mRNA structural barriers may impact on initiation efficiency. See text for details.
Figure 2
Figure 2
Model illustrating eIF4F activity residing within a Goldilocks zone to sustain optimal tumor cell survival. Given that eIF4F activity is critical for sustained output of key players in tumor cell initiation, maintenance, and metastasis, altering this activity can dramatically impact tumor cell fitness. See text for details.
See this image and copyright information in PMC

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