Targeting the eIF4A RNA helicase as an anti-neoplastic approach

• Many signaling pathways that are commonly deregulated during tumor progression converge to the regulation of mRNA translation.
• eIF4A is an essential translation initiation factor that facilitates the loading of the 43S preinitiation complex onto the mRNA.
• Natural products that specifically inhibit eIF4A activity have been found to be potent anti-tumorigenic agents in pre-clinical studies.

Protein synthesis is an essential cellular process that is highly responsive to extra- and intracellular cues such as mitogens, growth signals, nutrient and energy status, and stress. Much regulation of translation is directed towards initiation, more specifically the ribosome recruitment phase which requires the eukaryotic initiation factor (eIF) 4 F complex to prepare the mRNA for the incoming 40S ribosome (and associated factors). As many commonly deregulated signaling pathways found in cancers converge to influence protein synthesis, targeting factors involved in translation initiation is a viable anti-neoplastic strategy that has demonstrated success in pre-clinical settings. Furthermore, transcripts that are particularly sensitive to fluctuations in levels of the eIF4F complex are often associated with oncogenic characteristics (eg proliferation, survival, and angiogenesis) and their translational output appears to be preferentially reduced when eIF4F is inhibited. In particular, the enzymatic subunit of the eIF4F complex, eIF4A, has been extensively explored as a druggable target with several natural products identified as potent and selective inhibitors. In this review, we discuss the cellular regulation of eIF4A activity and its potential as a therapeutic target. This article is part of a Special Issue entitled: Translation and Cancer.