Translational Control in Cancer Etiology

Abstract

The link between perturbations in translational control and cancer etiology is becoming a primary focus in cancer research. It has now been established that genetic alterations in several components of the translational apparatus underlie spontaneous cancers as well as an entire class of inherited syndromes known as "ribosomopathies" associated with increased cancer susceptibility. These discoveries have illuminated the importance of deregulations in translational control to very specific cellular processes that contribute to cancer etiology. In addition, a growing body of evidence supports the view that deregulation of translational control is a common mechanism by which diverse oncogenic pathways promote cellular transformation and tumor development. Indeed, activation of these key oncogenic pathways induces rapid and dramatic translational reprogramming both by increasing overall protein synthesis and by modulating specific mRNA networks. These translational changes promote cellular transformation, impacting almost every phase of tumor development. This paradigm represents a new frontier in the multihit model of cancer formation and offers significant promise for innovative cancer therapies. Current research, in conjunction with cutting edge technologies, will further enable us to explore novel mechanisms of translational control, functionally identify translationally controlled mRNA groups, and unravel their impact on cellular transformation and tumorigenesis.

Biological Relevance and Therapeutic Potential of the Hypusine Modification System

“…As current studies highlight that eIF-5A2 has additional transcriptional activity (24), it can be assumed that eIF-5A1 might have similar nuclear activity, which is responsible for its strong phenotype. It is common knowledge that tumor cells accelerate their translational activity to adapt to the increasing cellular demands (2). Accordingly, previous work unveiled that the hypusine modification system is frequently overexpressed in cancer tissue (16,17,70), supporting the hypothesis that eIF-5A facilitates translation of genes with tumor promoting activity as described for other translation factors (71).…”

“…In addition to the important role in normal physiology, there is accumulating evidence that alterations in the translation machinery (e.g. deregulated translation factors) lead to changes in protein biosynthesis and the development or progression of various diseases like cancer and viral infections (2,3). Given that translation factors are frequently regulated by post-translational modifications, which are mediated by enzymes, those modifications can be harnessed therapeutically (4).…”

Reversible induction of translational isoforms of p53 in glucose deprivation

“…Deregulations in translational control contribute to each step of cellular transformation and tumor progression, nutrient starvation being a very common stress for the cells located inside non-vascularized tumors. 61 Activation of p53 IRESs on glucose deprivation provides a new regulatory aspect to the field of translational control of p53 mRNA, suggesting critical function of the p53 isoforms in these conditions in terms of cell survival and stress tolerance.…”

Pharmacological eEF 2K activation promotes cell death and inhibits cancer progression

“…It is possible that eEF2K activation may lead to exceed the acceptable threshold of overall translation inhibition or may specifically alter the repertoire of translated genes by preferentially affecting survival and proliferation factors. Malignant cells exhibit altered translational programming that is characterized by augmented activity of many components of the translation machinery, leading to increased overall protein synthesis and modulation of specific oncogenic networks [46]. This was shown, for example, in mice engineered to carry only a single copy of the translation initiation factor eIF4E gene [47].…”