The eIF4E2-Directed Hypoxic Cap-Dependent Translation Machinery Reveals Novel Therapeutic Potential for Cancer Treatment

Figure 2

Summary of current therapeutic strategies targeting eIF4F and possible therapeutic interventions for eIF4F^H. (a) Rapamycin and asTORi inhibit mTORC1, allowing hypophosphorylated 4E-binding protein (4EBP) to block the eukaryotic initiation factor 4E (eIF4E) binding site from eIF4G. Inhibitors that degrade Mnk1 kinase prevent eIF4E phosphorylation, which reduces tumor growth. The most promising therapeutics includes eIF4E suppression via antisense oligonucleotides (ASOs) and disrupting the eIF4E-eIF4G interaction with drugs such as 4EGI-1. Inhibiting the eIF4A RNA helicase has displayed high preclinical potency, especially silvestrol, in mouse models of tumor progression. (b) Current evidence demonstrates that suppression of eIF4E2 via lentiviral-delivered shRNAs is effective at stalling or reversing tumor growth in mouse xenografts of several different cancer cell lines. Drugs used to target eIF4F such as 4EGI-1 and silvestrol could potentially also inhibit eIF4F^H through blocking the eIF4E2-eIF4G3 interaction or inhibiting eIF4A, respectively. (c) The 3′ UTR RNA hypoxia response element (rHRE) that is found in eIF4E2-dependent transcripts could be exploited as a hypoxia-inducible RNA sequence. The rHRE would repress synthesis until the therapeutic RNA reaches the hypoxic tumor cells. This would be especially useful when paired with a suicide gene, for example.

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