Targeting the Human 80S Ribosome in Cancer: From Structure to Function and Drug Design for Innovative Adjuvant Therapeutic Strategies

Abstract

The human 80S ribosome is the cellular nucleoprotein nanomachine in charge of protein synthesis that is profoundly affected during cancer transformation by oncogenic proteins and provides cancerous proliferating cells with proteins and therefore biomass. Indeed, cancer is associated with an increase in ribosome biogenesis and mutations in several ribosomal proteins genes are found in ribosomopathies, which are congenital diseases that display an elevated risk of cancer. Ribosomes and their biogenesis therefore represent attractive anti-cancer targets and several strategies are being developed to identify efficient and specific drugs. Homoharringtonine (HHT) is the only direct ribosome inhibitor currently used in clinics for cancer treatments, although many classical chemotherapeutic drugs also appear to impact on protein synthesis. Here we review the role of the human ribosome as a medical target in cancer, and how functional and structural analysis combined with chemical synthesis of new inhibitors can synergize. The possible existence of oncoribosomes is also discussed. The emerging idea is that targeting the human ribosome could not only allow the interference with cancer cell addiction towards protein synthesis and possibly induce their death but may also be highly valuable to decrease the levels of oncogenic proteins that display a high turnover rate (MYC, MCL1). Cryo-electron microscopy (cryo-EM) is an advanced method that allows the visualization of human ribosome complexes with factors and bound inhibitors to improve our understanding of their functioning mechanisms mode. Cryo-EM structures could greatly assist the foundation phase of a novel drug-design strategy. One goal would be to identify new specific and active molecules targeting the ribosome in cancer such as derivatives of cycloheximide, a well-known ribosome inhibitor.

Structural Heterogeneities of the Ribosome: New Frontiers and Opportunities for Cryo-EM

“…To investigate the role of the ribosome in tumor and ribosomopathies [ 38 , 39 ], mutational surveys and genetic screenings have more generally identified specific sites and regions of the ribosome structure, which can serve as primary targets for drug treatment. Although there are still some limitations due to the low throughput of the technique and time to obtain structure at high resolution, using cryo-EM can explain how specific ligands can bind to ribosomes and inhibit their activity, offering a new perspective for structure-based drug design [ 40 , 41 ].…”

“…While this approach has been relatively recent in human [ 41 , 42 , 43 , 44 ], the determination of complex ribosomal structures with binding drugs has been an intense subject of study in bacteria. Superimposition and comparison with regular structures have explained how antibiotic drugs can target and modify specific sites of the ribosome, to interfere with different key steps during translation [ 45 ].…”

Ribosome Biogenesis Alterations in Colorectal Cancer

“…The rationale for targeting ribosome biogenesis in cancer is based on experimental and clinical evidence showing that tumorigenesis is associated with quantitative increases in ribosome production and/or production of qualitatively-altered ribosome species [44,45,47,48,52,[170][171][172][173]. These characteristics have formed the basis for the development of new drugs that disrupt the activation of rRNA synthesis by directly targeting the formation and activity of the RNA pol I transcriptional complex on rDNA [51,[174][175][176].…”

Knockdown of the Ribosomal Protein eL29 in Mammalian Cells Leads to Significant Changes in Gene Expression at the Transcription Level

“…Ribosomal proteins play a pivotal role in maintaining the architecture of large (60S) and small (40S) ribosomal subunits and are involved in the operation of the translational machinery, being its constituents [1][2][3][4][5]. A typical mammalian ribosome contains 80 individual ribosomal proteins [5], most of which are essential for cell viability.…”

“…Ribosomal proteins play a pivotal role in maintaining the architecture of large (60S) and small (40S) ribosomal subunits and are involved in the operation of the translational machinery, being its constituents [1][2][3][4][5]. A typical mammalian ribosome contains 80 individual ribosomal proteins [5], most of which are essential for cell viability. The deficiency of ribosomal proteins in cells usually causes significant disturbances in the processing of rRNA and the assembly of ribosomal subunits, which leads to a reduction in the population of ribosomes and, as a consequence, to a decrease in the rate of protein synthesis [6][7][8].…”