Abstract: It was previously believed that the level of transcription was the decisive factor in determining how much of a gene was expressed. Advances in high-throughput technologies have systematically deepened our understanding of the quantitative relationship between transcripts and proteins in a wide range of systems and conditions, and it turned out that the abundance of mRNAs is not always consistent with that of their encoded proteins, especially under cellular stress. This highlights the critical roles of post-transcriptional regulation in gene expression, and as expected, mRNA translation, the ultimate step of protein synthesis, is indispensable for cells to function, to proliferate, and to adapt. Tumor progression often faces more complex and severe microenvironmental challenges, such as nutritional shortages, immune attacks and that from anti-tumor drugs. In this respect, mRNA translation offers a rapid synthesis of functional proteins, which is particularly important for cell adaptation and survival. In addition, the high proliferation rate of tumor cells also makes them more demanding for protein synthesis. Thus, targeting the oncogenic translation control may serve as a potent therapeutic option that can both abrogate tumor progressions and help overcome drug resistances.
A variety of tumors have been shown to have aberrant activation of translational regulation, as indicated by excessive activation of upstream oncogenic signaling pathways, like PI3K-AKT, RAS-MAPK and Myc. Selective oncogenic mRNA translation is triggered downstream of these oncogenic signaling pathway, which promotes both the expression and activity of the eukaryotic translation initiation complex eIF4F, thereby facilitating translation, especially in tumors driven by oncogenes such as Myc and Ras. Despite the pivotal role of translational control in the development of tumor, there are very few anti-tumor drugs targeting this process in the clinic. Among them, mTOR inhibitors are currently the only FDA-approved molecular targeted drugs in clinic that block tumor mRNA translation and exhibit potent inhibitory effects in a wide range of tumors. Like other anti-tumor drugs, resistance to mTOR inhibitors may happen. To overcome their resistance, mTOR inhibitors have been optimized over several generations, which have shown significant improvements in bioavailability, anti-metastatic activity, and anti-tumor efficacy. However, as the mTOR signaling pathway is the upstream of the entire translation machinery, its anti-tumor effect remains likely to be impeded by the aberrant expression and activation of the downstream translation factors. With the emerging of molecular targeted therapy, the design of compounds specifically targeting downstream translation factors has become a new trend, particularly for those responsible for the translation initiation (e.g. eIF4 proteins), the rate-limiting step of the translation processes. In fact, several small-molecule inhibitors specifically targeting the translation machinery have been developed and some are already in clinical trials at various phases, such as eFT508, a potent and selective small-molecule inhibitor targeting the kinase of eIF4E, currently in phase II clinical trial for colorectal and castration-resistant prostate cancers, and the eIF4A inhibitor Zotatifin in a Phase I/II study in patients with advanced breast cancer and non-small cell lung cancer.
In this review, we briefly discuss aspects that control the translation process, which involves translation factors, ribosomes, tRNAs, secondary structure of mRNAs and etc.. Furthermore, we highlight in detail how different stages of translation are hijacked in tumor cells to adapt to the variable microenvironments and facilitate malignant progression. We also focus on the aberrant activation of signaling pathways in tumor cells as well as the expression and activation of translational factors, which are important for tumor proliferation, survival, angiogenesis and metastasis. Finally, we summarize the existing compounds targeting these factors, and provide an overview of their promising preclinical and clinical applications.