Translation Regulation as a Therapeutic Target in Cancer

Abstract

Protein synthesis is a vital cellular process that regulates growth and metabolism. It is controlled via signaling networks in response to environmental changes, including the presence of nutrients, mitogens, or starvation. The phosphorylation state of proteins involved in translation initiation is a limiting factor that regulates the formation or activity of translational complexes. In cancer cells, hyperactivated signaling pathways influence translation, allowing uncontrolled growth and survival. In addition, several components of translation initiation have been found to be mutated, posttranslationally modified, or differentially expressed, and some act as oncogenes in cancer cells. Translational alterations can increase the overall rate of protein synthesis as well as activate regulatory mechanisms leading to the translation of specific messenger RNAs for proteins that promote cancer progression and survival. Many recent studies investigating such mechanisms have produced ideas for therapeutic intervention. This review describes altered mechanisms of protein synthesis in human cancers and discusses therapeutic approaches based on the targeting of translation. Cancer Res; 72(16); 3891-900. Ó2012 AACR.

AMP Kinase Activation Alters Oxidant-Induced Stress Granule Assembly by Modulating Cell Signaling and Microtubule Organization

“…The new insights presented here are important because they are relevant to different human diseases. For example, AMPK activation can interfere with tumor cell proliferation, notably by affecting translation (Grzmil and Hemmings, 2012;Chen et al, 2014). On the other hand, SGs are formed by some types of cancer, where they promote tumor survival and progression (Thedieck et al, 2013;Somasekharan et al, 2015).…”

Functional Profiling of Receptor Tyrosine Kinases and Downstream Signaling in Human Chondrosarcomas Identifies Pathways for Rational Targeted Therapy

“…A detailed comparison of the effects of these three inhibitors on PI3K/ mTOR signaling showed that BEZ235 is a more potent inhibitor of the phosphorylation of S6 and 4EBP1, important regulators of global protein synthesis and cap-dependent protein translation, respectively (39). Increases in the overall rate of protein synthesis as well as enhanced translation of oncogenes are often driven by the hyperactivation of RTKs and their downstream effectors, allowing uncontrolled growth and survival of cancer cells (40). The ability of BEZ235 to inhibit S6 and 4EBP1 phosphorylation both in vitro and in vivo may account for its potent antitumor activity in chondrosarcoma as well as in other cancer types (41,42).…”

MNK1 pathway activity maintains protein synthesis in rapalog-treated gliomas

“…Activated mTORC1 is composed of mTOR kinase, the adaptor protein raptor, and mLST8 and supports protein synthesis by the phosphorylation of eukaryotic translation initiation factor 4E-binding (eIF4E-binding) proteins (4EBPs), translation initiation factor scaffold protein eIF4G, and S6 kinase (S6K), as reviewed recently (6)(7)(8). Active S6K phosphorylates ribosomal protein S6 and RNA helicase cofactor eIF4B and inactivates eEF2 kinase (eEF2K), which inhibits elongation factor eEF2 as well as translation inhibitor programmed cell death 4 (PDCD4) by inducing its proteasomal degradation.…”