Ribosome biogenesis: An emerging druggable pathway for cancer therapeutics

Catez, Frédéric; Venezia, Nicole Dalla; Marcel, Virginie; Zorbas, Christiane; Lafontaine, Denis L. J.; Diaz, Jean‐Jacques

doi:10.1016/j.bcp.2018.11.014

Cited by 122 publications

(110 citation statements)

References 97 publications

(161 reference statements)

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“…Ribosomes are associated with bone marrow failure, skeletal and other developmental abnormalities, immune signaling, and cancer predisposition, 27‐30 and are overexpressed in several cancers such as hepatocellular cancer and gastric cancer 31,32 . Moreover, downregulation of ribosomal proteins reportedly suppresses tumorigenesis and progression, 33 suggesting that ribosomes constitute a potential target for cancer treatment 34,35 …”

Section: Discussionmentioning

confidence: 99%

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Ribosomal protein S6 promotes stem‐like characters in glioma cells

et al. 2020

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Glioblastoma multiforme (GBM), a lethal brain tumor developing in the white matter of the adult brain, contains a small population of GBM stem cells (GSCs), which potentially cause chemotherapeutic resistance and tumor recurrence. However, the mechanisms underlying the pathogenesis and maintenance of GSCs remain largely unknown. A recent study reported that incorporation of ribosomes and ribosomal proteins into somatic cells promoted lineage trans‐differentiation toward multipotency. This study aimed to investigate the mechanism underlying stemness acquisition in GBM cells by focusing on 40S ribosomal protein S6 (RPS6). RPS6 was significantly upregulated in high‐grade glioma and localized at perivascular, perinecrotic, and border niches in GBM tissues. siRNA‐mediated RPS6 knock‐down significantly suppressed the characteristics of GSCs, including their tumorsphere potential and GSC marker expression; STAT3 was downregulated in GBM cells. RPS6 overexpression enhanced the tumorsphere potential of GSCs and these effects were attenuated by STAT3 inhibitor (AG490). Moreover, RPS6 expression was significantly correlated with SOX2 expression in different glioma grades. Immunohistochemistry data herein indicated that RPS6 was predominant in GSC niches, concurrent with the data from IVY GAP databases. Furthermore, RPS6 and other ribosomal proteins were upregulated in GSC‐predominant areas in this database. The present results indicate that, in GSC niches, ribosomal proteins play crucial roles in the development and maintenance of GSCs and are clinically associated with chemoradioresistance and GBM recurrence.

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Section: Discussionmentioning

confidence: 99%

“…The nucleolus is larger in malignant than in not‐malignant cancer cells 33 . A recent study reported that translation of rRNA and nucleolar regulation promote glioma tumorigenesis 33‐35,38 …”

Section: Discussionmentioning

confidence: 99%

Ribosomal protein S6 promotes stem‐like characters in glioma cells

et al. 2020

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“…The development of optogenetic approaches to engineer the assembly of de novo condensates (25)(26)(27)(28), and now to modulate the properties of endogenous ones, promises to have an enormous impact on our understanding of these emerging links between the material properties and (dys)function of the nucleolus. These insights will suggest new therapeutic approaches for tackling ribosome disorders by modulating nucleolar assembly and material properties, adding novel options to the developing arsenal targeting the nucleolus for anticancer intervention (54).…”

Section: Discussionmentioning

confidence: 99%

Controlling the material properties and rRNA processing function of the nucleolus using light

Zhu

Richardson

Wacheul

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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The nucleolus is a prominent nuclear condensate that plays a central role in ribosome biogenesis by facilitating the transcription and processing of nascent ribosomal RNA (rRNA). A number of studies have highlighted the active viscoelastic nature of the nucleolus, whose material properties and phase behavior are a consequence of underlying molecular interactions. However, the ways in which the material properties of the nucleolus impact its function in rRNA biogenesis are not understood. Here we utilize the Cry2olig optogenetic system to modulate the viscoelastic properties of the nucleolus. We show that above a threshold concentration of Cry2olig protein, the nucleolus can be gelled into a tightly linked, low mobility meshwork. Gelled nucleoli no longer coalesce and relax into spheres but nonetheless permit continued internal molecular mobility of small proteins. These changes in nucleolar material properties manifest in specific alterations in rRNA processing steps, including a buildup of larger rRNA precursors and a depletion of smaller rRNA precursors. We propose that the flux of processed rRNA may be actively tuned by the cell through modulating nucleolar material properties, which suggests the potential of materials-based approaches for therapeutic intervention in ribosomopathies.

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“…A lack of proper ribosome biogenesis is associated with the production of free RPs, a prototype being ribosomal protein uL5, that then interacts with HDM2/MDM2, interfering with its function to degrade p53, preventing a tumor-suppressive response [54,55]. Ribosome biogenesis is therefore considered as an attractive anti-cancer target [56]. As a matter of fact, it has been realized that interference with ribosome biogenesis was part of the anti-cancer properties of several classic anti-neoplastic drugs, even if the ribosome was not considered as their primary target [57].…”

Section: Targeting Ribosome Biogenesismentioning

confidence: 99%

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

Gilles

Fréchin

Natchiar

et al. 2020

Cells

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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.

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Ribosome biogenesis: An emerging druggable pathway for cancer therapeutics

Cited by 122 publications

References 97 publications

Ribosomal protein S6 promotes stem‐like characters in glioma cells

Ribosomal protein S6 promotes stem‐like characters in glioma cells

Controlling the material properties and rRNA processing function of the nucleolus using light

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

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