Targeting the Eukaryotic Translation Initiation Factor 4E for Cancer Therapy

Abstract

The eukaryotic translation initiation factor 4E (eIF4E) is frequently overexpressed in human cancers in relation to disease progression and drives cellular transformation, tumorigenesis, and metastatic progression in experimental models. Enhanced eIF4E function results from eIF4E overexpression and/or activation of the ras and phosphatidylinositol 3-kinase/AKT pathways and selectively increases the translation of key mRNAs involved in tumor growth, angiogenesis, and cell survival. Consequently, by simultaneously and selectively reducing the expression of numerous potent growth and survival factors critical for malignancy, targeting eIF4E for inhibition may provide an attractive therapy for many different tumor types. Recent work has now shown the plausibility of therapeutically targeting eIF4E and has resulted in the advance of the first eIF4E-specific therapy to clinical trials. These studies illustrate the increased susceptibility of tumor tissues to eIF4E inhibition and support the notion that the enhanced eIF4E function common to many tumor types may represent an Achilles' heel for cancer. [Cancer Res 2008;68(3):631-4] eIF4E Function and mRNA Discrimination Eukaryotic translation initiation factor 4E (eIF4E) binds the 5 ¶,7-methylguanosine cap structure of mRNAs, delivering these mRNAs to the eIF4F translation initiation complex, which is composed of eIF4E, the scaffolding protein eIF4G, and the ATPdependent RNA helicase eIF4A. The eIF4F complex then scans through the 5 ¶ untranslated region (UTR), unwinding mRNA secondary structure to expose the translation initiation codon and enable translation (1). eIF4F complex assembly is rate limiting for translation initiation and is largely dependent on eIF4E availability. Under normal cellular conditions, eIF4F complex assembly is limited as eIF4E is sequestered from eIF4G by binding to 4E binding proteins (4EBP). Stimulation of the phosphatidylinositol 3-kinase/AKT/mTOR pathway leads to hierarchical 4EBP phosphorylation, dislodging 4EBP from eIF4E and enabling assembly of the eIF4F complex (1).Enhanced eIF4F complex formation increases the translation of all cap-dependent mRNAs and thereby increases global protein synthesis rates. However, mRNAs vary widely in their inherent ''translatability, '' largely as a function of differences in the length and structure of their 5 ¶ UTRs. Cellular mRNAs most sensitive to alterations in eIF4E availability and eIF4F complex formation (i.e., weak mRNAs) have lengthy, G+C rich, highly structured 5 ¶ UTRs that encumber efficient RNA unwinding by eIF4F and subsequently prevent ribosome loading. Consequently, these mRNAs are most sensitive to eIF4E availability and are poorly translated under normal conditions when eIF4F complex formation is limiting. In contrast, most cellular mRNAs have relatively short, unstructured 5 ¶ UTRs (e.g., h-actin) that enable efficient scanning, initiation codon recognition, and ribosome loading and translation even when eIF4F complex levels are limiting. Whereas strong mRNAs (such as h-act...

Reversing chemoresistance by small molecule inhibition of the translation initiation complex eIF4F

“…Because 4E-BPs and eIF4G (there are two isoforms, called eIF4GI and eIF4GII, that share all structural features and show 46% sequence identity) compete for binding to a common site on eIF4E, 4E-BP binding to eIF4E decreases its availability for incorporation into the eIF4F complex and reduces translation initiation rates-with modest consequences on global translation but more pronounced effects on translation of specific mRNAs (1). This discriminatory effect on translation initiation is dependent on the amount of secondary structure present in the 5′ UTRs of mRNAs-with mRNAs harboring more secondary structure being more dependent on eIF4F for ribosome loading (2,3). Gene expression profiling has identified mRNA transcripts whose translation is preferentially stimulated by altered eIF4E levels, indicating that eIF4E can affect the expression of a large gene set that impinge on several signaling nodes.…”

MicroRNA-214 Reduces Insulin-like Growth Factor-1 (IGF-1) Receptor Expression and Downstream mTORC1 Signaling in Renal Carcinoma Cells

“…However, a recent report established a significant contribution of 4EBP-1 in mammalian cell proliferation. mTORC1-mediated phosphorylation of 4EBP-1 releases eIF4E, which forms the eIF4F complex and regulates translation of a subset of mRNAs necessary for cell proliferation, including VEGF (82)(83)(84). Increased VEGF expression in VHL-deficient RCC is mainly mediated by stabilized Hif2␣-mediated transcription (51).…”

Potential therapeutic targets for chordoma: PI3K/AKT/TSC1/TSC2/mTOR pathway

“…Nevertheless, our findings provide an evidence base for treating selected chordomas with mTOR, AKT inhibitors and antisense molecules to the attractive cancer target, eIF-4E (Graff et al, 2008). A combination of agents, rather than individual drugs, is more likely to offer therapeutic success particularly as there is evidence that AKT is activated at ser473 by TORC2, a rapamycin-insensitive molecule (Sarbassov et al, 2005).…”