Targeting the Human 80S Ribosome in Cancer: From Structure to Function and Drug Design for Innovative Adjuvant Therapeutic Strategies.
Fiche publication
Date publication
mars 2020
Journal
Cells
Auteurs
Membres identifiés du Cancéropôle Est :
Dr KLAHOLZ Bruno
Tous les auteurs :
Gilles A, Frechin L, Natchiar K, Biondani G, Loeffelholz OV, Holvec S, Malaval JL, Winum JY, Klaholz BP, Peyron JF
Lien Pubmed
Résumé
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.
Mots clés
antibiotics, cancer, leukemia, ribosome, targeted therapies
Référence
Cells. 2020 Mar 5;9(3):