Targeting eIF4F in cancer

eIF4F is composed of eukaryotic translation initiation factors of cap-binding protein eIF4E, scaffolding protein eIF4G and RNA helicase eIF4A [3].eIF4F complex assembly is essential for the recruitment of mRNAs to the ribosomes during the initiation stage, the rate-limiting step in translation [4,5]. Many oncogenic mRNAs, which encode oncoproteins with low abundance while important for cancer cell survival, proliferation and growth, contain long and /or highly structured 5’-untranslated regions (5’-UTRs) with low translational efficiency (Figure 1) [6]. The increased eIF4F activities is critical for the upregulation of translation of oncogenic mRNAs to produce sufficient proteins to support cancer cells’ apoptosis escaping, resistance to radio-/chemical therapy, uncontrolled proliferation, and aggressive metastasis [7].Therefore, interfering eIF4F activities provides unique opportunities to selectively suppress the translation of oncogenic mRNAs with low translational efficiency while leave the non-oncogenic mRNAs with high translational efficiency. Indeed, studies have found that inhibiting eIF4F complex assembly preferentially suppresses cancerous cells. The translation initiation factors eIF4E-eIF4G interaction inhibitor 4EGI-1 binds to eIF4E,induces allosteric effects to the eIF4G interacting sites on eIF4E, and therefore prevents eIF4G recruitment to eIF4E and enhances 4E-BP1 binding to eIF4E [8]. 4E-BP1 binding to eIF4E further prevents eIF4F assembly [9]. 4EGI-1consistently inhibits multiple cancer cell lines as well as cancer stem cells with enhanced drug resistance [10,11].


Editorial
To overcome innate and acquired drug resistance in cancer treatment is a challenge.Translation initiation complex of eIF4F appears to be a promising target for overwhelming drug resistance in the pharmaceutical therapy against cancer [1,2].eIF4F is composed of eukaryotic translation initiation factors of cap-binding protein eIF4E, scaffolding protein eIF4G and RNA helicase eIF4A [3].eIF4F complex assembly is essential for the recruitment of mRNAs to the ribosomes during the initiation stage, the rate-limiting step in translation [4,5].Many oncogenic mRNAs, which encode oncoproteins with low abundance while important for cancer cell survival, proliferation and growth, contain long and /or highly structured 5'-untranslated regions (5'-UTRs) with low translational efficiency (Figure 1) [6].The increased eIF4F activities is critical for the upregulation of translation of oncogenic mRNAs to produce sufficient proteins to support cancer cells' apoptosis escaping, resistance to radio-/chemical therapy, uncontrolled proliferation, and aggressive metastasis [7].Therefore, interfering eIF4F activities provides unique opportunities to selectively suppress the translation of oncogenic mRNAs with low translational efficiency while leave the non-oncogenic mRNAs with high translational efficiency.
Indeed, studies have found that inhibiting eIF4F complex assembly preferentially suppresses cancerous cells.The translation initiation factors eIF4E-eIF4G interaction inhibitor 4EGI-1 binds to eIF4E,induces allosteric effects to the eIF4G interacting sites on eIF4E, and therefore prevents eIF4G recruitment to eIF4E and enhances 4E-BP1 binding to eIF4E [8].4E-BP1 binding to eIF4E further prevents eIF4F assembly [9].4EGI-1consistently inhibits multiple cancer cell lines as well as cancer stem cells with enhanced drug resistance [10,11].
Several studies have shown that targeting eIF4F can effectively overwhelm acquired drug resistance in tumors.For instance, the inhibition of eIF4F complex, either by blocking the eIF4E-eIF4G interaction or by targeting eIF4A, synergizes with drugs targeting BRAF (V600) and/or MEK to overcome drug resistance relying on multiple signaling pathways, and to kill BRAF(V600) tumor cells [12,13].
The regulation of the assembly of eIF4F complex, either by protein-protein interaction (PPI)mediation or by factor availability control, is the nexus in mediating the translation initiation apparatus.The eIF4F complex not only appears to be an indicator of both innate and acquired resistance but also is a promising therapeutic target in cancer treatment.Targeting eIF4F may overcome: 1) inherent resistance to drugs targeting one or a few oncoproteins, which is caused by cancer cell heterogeneity and/or compensation of diverse/redundant oncoproteins in a type of cancer cell; and 2) acquired resistance due to mutations after drug treatment [14].
Even though the eIF4F controlled cap-dependent translation is the major format of protein biosynthesis,internal ribosome entry site (IRES)-dependent translation produces some proteins important for cancer cell survival, proliferation and metastasis.Therefore, future pharmaceutical strategies, such as the control of both cap-dependent and IRES-dependent translation of oncogenic mRNAs, should be taken to increase the synergic effects in selectively getting rid of cancer cells and eradicating cancer stem cells.