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

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Targeting the Human 80S Ribosome in Cancer: from Structure to Function and Drug Design for Innovative Adjuvant Therapeutic Strategies cells Review Targeting the Human 80S Ribosome in Cancer: From Structure to Function and Drug Design for Innovative Adjuvant Therapeutic Strategies Arnaud Gilles 1,Léo Frechin 2, Kundhavai Natchiar 2, Giulia Biondani 3, Ottilie von Loeffelholz 2 , Samuel Holvec 2, Julie-Lisa Malaval 1 , Jean-Yves Winum 1,* , Bruno P. Klaholz 2,* and Jean-François Peyron 3,* 1 IBMM, Univ Montpellier, CNRS, IBMM, ENSCM, 34296 Montpellier, France; [email protected] (A.G.); [email protected] (J.-L.M.) 2 Université de Strasbourg, CNRS, Inserm, Centre for Integrative Biology, IGBMC, 67404 Illkirch, France; [email protected] (L.F.); [email protected] (K.N.); loeff[email protected] (O.v.L.); [email protected] (S.H.) 3 Université Côte d’Azur, Inserm, C3M, 06204 Nice, France; [email protected] * Correspondence: [email protected] (J.-Y.W.); [email protected] (B.P.K.); [email protected] (J.-F.P.) Received: 23 January 2020; Accepted: 2 March 2020; Published: 5 March 2020 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. Keywords: ribosome; cancer; leukemia; antibiotics; targeted therapies 1. Introduction In normal cells, protein synthesis (PS) is tightly linked to their proliferative needs [1,2]. In contrast, cancer cells have enslaved protein synthesis mechanisms to fuel their metabolic needs and a typical cancer cell expresses at least 10,000 different proteins [3], with PS being one of the most complex and energy-expensive cellular processes. All steps of PS are susceptible to dysregulation during cancer development, as previously reviewed [4,5]. Firstly, oncogenic signaling by mutated receptor tyrosine Cells 2020, 9, 629; doi:10.3390/cells9030629 www.mdpi.com/journal/cells CellsCells 20202020,, 99,, 629 629 2 2of of 22 22 during cancer development, as previously reviewed [4,5]. Firstly, oncogenic signaling by mutated receptorkinases (e.g.,tyrosine EGFR) kinases and (e.g., oncogenes EGFR) (e.g.,and oncogene MYC, RAS)s (e.g., can MYC, converge RAS) atcan mTORC1 converge to at stimulate mTORC1 theto stimulateinitiation ofthe PS. initiation Thereafter, of PS. initiation Thereafter, and elongation,initiation and two elongation important, two molecular important steps molecular of PS, can steps occur of at PS,increased can occur levels at andincreased this is achievedlevels and by this the dysregulatedis achieved by expression the dysregulated of important expression translation of important factors [6]. translationFor instance, factors theeukaryotic [6]. For instance, initiation the factor eukaryotic 4F complex initiation (eIF4F), factor which 4F complex is critical (eIF4F), to stimulate which the is criticalinitiation to stimulate of PS, controlled the initiation by growth of PS, factors, controlled is deregulated by growth infactors, cancer is cells. deregulated in cancer cells. TheThe eukaryotic eukaryotic ribosome ribosome is isthe the essential essential cellular cellular nucleoprotein nucleoprotein nanomachine nanomachine of 3.5 ofto 4.5 3.5 Mega- to 4.5 DaltonsMega-Daltons [7] (Figure [7] (Figure 1A,B)1 A,B)that thatdecodes decodes the thegenetic genetic information information carried carried by by mRNAs mRNAs into into proteins, proteins, establishingestablishing a a link link between between genes genes and and cellular cellular functi functions.ons. In In many, many, not not to to say say all all cancers, ribosome ribosome biogenesisbiogenesis is is enhanced enhanced to to face face the the important important need need for for proteins proteins by by proliferating proliferating cancer cancer cells cells [8]. [8]. As As it it isis the the central central element element of of protein protein synthesis, synthesis, it it has has b beeneen considered considered for for a a long long time time as as a a possible possible target target forfor anti-cancer anti-cancer molecules. molecules. This This review review specifically specifically focuses focuses on on the the renewed renewed interest interest in in targeting targeting the the cytosoliccytosolic human human 80S 80S (Svedberg (Svedberg co constant)nstant) ribosome in cancer. Figure 1. Structural analysis of the human 80S cytosolic ribosome. (A,B) Structure overview of the Figure 1. Structural analysis of the human 80S cytosolic ribosome. (A,B) Structure overview of the 40S 40S and 60S ribosomal subunits of the human ribosome (atomic model derived from the cryo-EM and 60S ribosomal subunits of the human ribosome (atomic model derived from the cryo-EM structure of the 80S human ribosome [9,10]. (C) Typical functional sites on the ribosome, which are structure of the 80S human ribosome [9,10]. (C) Typical functional sites on the ribosome, which are directly relevant for binding of inhibitors. (D) Detailed features in the high-resolution cryo-EM of the directly relevant for binding of inhibitors. (D) Detailed features in the high-resolution cryo-EM of the human 80S ribosome in which chemical modifications are visible [10]. (E) Structure of the human 80S human 80S ribosome in which chemical modifications are visible [10]. (E) Structure of the human 80S ribosome complex with the HHT inhibitor (the inset shows the cryo-EM mpa density corresponding to ribosome complex with the HHT inhibitor (the inset shows the cryo-EM mpa density corresponding the ligand). (F) Structure-based drug design: CHX as a case study; hydrogen bonds are indicated by to the ligand). (F) Structure-based drug design: CHX as a case study; hydrogen bonds are indicated dotted lines; eL42 is eukaryote-specific ribosomal protein which could be targeted to generate specificity byusing dotted chemically lines; eL42 modified is eukaryote-specific ligands. CP: central riboso protuberance;mal protein A: which aminoacyl could site; be P:targeted peptidyl to site; generate E: exit specificitysite. CHX: using cycloheximide; chemically HHT: modified homoharringtonine; ligands. CP: central EDE: protuberance; edeine. A: aminoacyl site; P: peptidyl site; E: exit site. CHX: cycloheximide; HHT: homoharringtonine; EDE: edeine. 2. The Human Ribosome 2. The Human Ribosome In the mid-1950s, the cell biologist George Palade (1974 Nobel prize) identified granules at the surfaceIn the of the mid-1950s, endoplasmic the cell reticulum biologist membrane George Palade as the sites (1974 of Nobel protein prize) synthesis identified in cells granules [11], that at were the surfacenamed of ribosomes the endoplasmic in 1958 [ 12reticulum]. At that membrane time, the firstas the theory sites emerged:of protein onesynthesis gene-one in cells ribosome-one [11], that wereprotein, named until ribosomes a couple of in years 1958 later [12]. it wasAt that realized time, that the ribosomes first theory were emerged: non-specialized one gene-one structures ribosome- which onesynthetize protein, proteins until froma couple a mRNA of years template. later Itit then was took realized several that decades ribosomes to understand were non-specialized that ribosomes structuresare highly which complex synthetize structures proteins and can from exist a as mRNA heterogeneous template. and It specializedthen took several entities [decades13]. It also to understand that ribosomes are highly complex structures and can exist as heterogeneous and Cells 2020, 9, 629 3 of 22 became clear that defects in ribosome function, regulation or composition, and more importantly, defects affecting protein synthesis, were involved in several human pathologies such as immunodeficiencies, metabolic disorders, neurological diseases, and particularly cancer (see [14] for an exhaustive review). A plethora of structural studies on ribosomes with small ligand-bound molecules has provided a rationale for mechanistic inhibition of translation. Translation inhibitors specifically target
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