The pleiotropic roles of eIF5A in cellular life and its therapeutic potential in cancer

Abstract

Protein synthesis is dysregulated in the majority of cancers and this process therefore provides a good therapeutic target. Many novel anti-cancer agents are directed to target the initiation stage of translation, however, translation elongation also holds great potential as a therapeutic target. The elongation factor eIF5A that assists the formation of peptidyl bonds during the elongation process is of considerable interest in this regard. Overexpression of eIF5A has been linked with the development of a variety of cancers and inhibitors of the molecule have been proposed for anti-cancer clinical applications. eIF5A is the only protein in the cell that contains the post-translational modification hypusine. Hypusination is a two-step enzymatic process catalysed by the Deoxyhypusine Synthase (DHPS) and Deoxyhypusine Hydroxylase (DOHH). In addition, eIF5A can be acetylated by p300/CBP-associated factor (PCAF) which leads to translocation of the protein to the nucleus and its deactivation. In addition to the nucleus, eIF5A has been found in the mitochondria and the endoplasmic reticulum (ER) with eIF5A localisation related to function from regulation of mitochondrial activity and apoptosis to maintenance of ER integrity and control of the unfolded protein response (UPR). Given the pleiotropic functions of eIF5A and by extension the hypusination enzymes, this system is being considered as a target for a range of cancers including multiple myeloma, B-Cell lymphoma, and neuroblastoma. In this review, we explore the role of eIF5A and discuss the therapeutic strategies that are currently developing both in the pre- and the clinical stage.