Translation acrobatics: how cancer cells exploit alternate modes of translational initiation

Abstract

Recent work has brought to light many different mechanisms of translation initiation that function in cells in parallel to canonical cap-dependent initiation. This has important implications for cancer. Canonical cap-dependent translation initiation is inhibited by many stresses such as hypoxia, nutrient limitation, proteotoxic stress, or genotoxic stress. Since cancer cells are often exposed to these stresses, they rely on alternate modes of translation initiation for protein synthesis and cell growth. Cancer mutations are now being identified in components of the translation machinery and in cis-regulatory elements of mRNAs, which both control translation of cancer-relevant genes. In this review, we provide an overview on the various modes of non-canonical translation initiation, such as leaky scanning, translation re-initiation, ribosome shunting, IRES-dependent translation, and m⁶A-dependent translation, and then discuss the influence of stress on these different modes of translation. Finally, we present examples of how these modes of translation are dysregulated in cancer cells, allowing them to grow, to proliferate, and to survive, thereby highlighting the importance of translational control in cancer.

Keywords: cancer; stress; translation initiation.

Figure 1. The canonical pathway of eukaryotic translation initiation

The figure shows a schematic representation of the canonical pathway of eukaryotic translation initiation, including the canonical initiation factors and signaling pathways that regulate these initiation factors.

Figure 2. Modes of translation

An overview of the various modes of mRNA translation is shown. For details, please refer to the main text.

Figure 3. Translational dysregulation in cancer

Non‐canonical translational mechanisms found in cancer cells are summarized. Red indicates down‐regulation, and blue indicates up‐regulation.