Changes in the translation of existing mRNAs can be more extensive than transcriptional changes that occur downstream of aberrant signaling pathways. Translational plasticity increases cancer cell fitness, leading to tumor formation and therapy resistance. This review highlights both the challenges and opportunities posed by the multifaceted and complex adaptations that occur in the control of translation in response to oncogenic stresses, such as hypoxia, neoangiogenesis, and growth dysregulation. Dysregulation of translation is a mutation-independent contributor to oncogenesis and reveals potential therapeutic targets.
Contributed by Margot O’Toole
ABSTRACT: Translational control of mRNAs during gene expression allows cells to promptly and dynamically adapt to a variety of stimuli, including in neoplasia in response to aberrant oncogenic signalling (for example, PI3K-AKT-mTOR, RAS-MAPK and MYC) and microenvironmental stress such as low oxygen and nutrient supply. Such translational rewiring allows rapid, specific changes in the cell proteome that shape specific cancer phenotypes to promote cancer onset, progression and resistance to anticancer therapies. In this Review, we illustrate the plasticity of mRNA translation. We first highlight the diverse mechanisms by which it is regulated, including by translation factors (for example, eukaryotic initiation factor 4F (eIF4F) and eIF2), RNA-binding proteins, tRNAs and ribosomal RNAs that are modulated in response to aberrant intracellular pathways or microenvironmental stress. We then describe how translational control can influence tumour behaviour by impacting on the phenotypic plasticity of cancer cells as well as on components of the tumour microenvironment. Finally, we highlight the role of mRNA translation in the cellular response to anticancer therapies and its promise as a key therapeutic target.