Ribosomes are a complex ensemble of rRNA and ribosomal proteins that function as mRNA translation machines. Ribosome biogenesis is a multistep process that begins in the nucleolus and concludes in the cytoplasm. The process is tightly controlled by multiple checkpoint and surveillance pathways. Perturbations in these checkpoints and pathways can lead to hyperactivation of ribosome biogenesis. Emerging evidence suggests that cancer cells harbor a specialized class of ribosomes (onco-ribosomes) that facilitates the oncogenic translation program, modulates cellular functions, and promotes metabolic rewiring. Mutations in ribosomal proteins, rRNA processing, and ribosome assembly factors result in ribosomopathies that are associated with an increased risk of developing malignancies. Recent studies have linked mutations in ribosomal proteins and aberrant ribosomes with poor prognosis, highlighting ribosome-targeted therapy as a promising approach for treating patients with cancer. Here, we summarize various aspects of dysregulation of ribosome biogenesis and the impact of resultant onco-ribosomes on malignant tumor behavior, therapeutic resistance, and clinical outcome. Ribosome biogenesis is a promising therapeutic target, and understanding the important determinants of this process will allow for improved and perhaps selective therapeutic strategies to target ribosome biosynthesis.

Aberrant cell growth and proliferation depend on increased protein synthesis and overactive translation that requires hyperactive ribosome biogenesis. This is enabled by multiple cellular regulatory pathways that are hijacked to tune transcription and translation (1). This is consistent with the acquisition of genetic and epigenetic alterations by cancer cells and changes in regulatory layers of translation such as microRNAs, tRNA modifications, and RNA-binding proteins that play significant roles during tumor progression and metastasis.

Ribosome biogenesis is a multistep process that starts in the nucleolus and culminates in the formation of functional ribosomes in the cell. Ribosomes serve as translation machinery in the cell and are a complex assembly of rRNAs and a large number of ribosomal proteins and ribosome-associated proteins. In humans, ribosomes comprise a small 40S subunit and a large 60S subunit. The small 40S subunit comprises 1 18S rRNA and 33 ribosomal proteins, while the large 60S subunit contains one each of the 28S, 5.8S, and 5S rRNAs and 47 ribosomal proteins. Together, the 60S and 40S subunits constitute the 80S ribosome particle (Fig. 1).

Figure 1.

Ribosome heterogeneity plays a role in tumorigenesis and cancer progression. Ribosome biogenesis begins in the nucleolus where repeats of rDNA reside. RNA Pol I transcription factors, such as UBTF and SL1 bind to active clusters of rDNAs to initiate RNA Pol I transcription and pre-rRNA biosynthesis. Then, pre-rRNA passes through a series of processing and rRNA modifications. Processed rRNA species are combined with ribosomal proteins to generate pre-60S and pre-40s subunits, which are matured and transported to the cytoplasm to participate in protein synthesis. Owing to their uncontrollable proliferation and high demand for ribosomes, cancer cells have upregulated activity of RNA Pol I, leading to increased rRNA biogenesis. In cancer, there are also noncanonical or abnormal rRNA modifications. Ribosomal proteins undergo posttranslational modifications. Differentially modified ribosome proteins can be incorporated in the ribosomes adding to the ribosome heterogeneity. In addition, ribosomal proteins, due to their extraribosomal functions, can contribute to chemo/radioresistance and cancer progression. It is hypothesized that all these alterations and modifications create “onco-ribosomes,” which carry out an aberrant translational program and direct the preferential translation of oncogenes and prosurvival genes that promote cancer progression.

Figure 1.

Ribosome heterogeneity plays a role in tumorigenesis and cancer progression. Ribosome biogenesis begins in the nucleolus where repeats of rDNA reside. RNA Pol I transcription factors, such as UBTF and SL1 bind to active clusters of rDNAs to initiate RNA Pol I transcription and pre-rRNA biosynthesis. Then, pre-rRNA passes through a series of processing and rRNA modifications. Processed rRNA species are combined with ribosomal proteins to generate pre-60S and pre-40s subunits, which are matured and transported to the cytoplasm to participate in protein synthesis. Owing to their uncontrollable proliferation and high demand for ribosomes, cancer cells have upregulated activity of RNA Pol I, leading to increased rRNA biogenesis. In cancer, there are also noncanonical or abnormal rRNA modifications. Ribosomal proteins undergo posttranslational modifications. Differentially modified ribosome proteins can be incorporated in the ribosomes adding to the ribosome heterogeneity. In addition, ribosomal proteins, due to their extraribosomal functions, can contribute to chemo/radioresistance and cancer progression. It is hypothesized that all these alterations and modifications create “onco-ribosomes,” which carry out an aberrant translational program and direct the preferential translation of oncogenes and prosurvival genes that promote cancer progression.

Close modal

The nucleolus is the principal site of ribosome biogenesis and forms around nucleolar organizer regions (NOR), which contain several hundred rDNA gene repeats in human diploid cells. These are located on each of the five acrocentric chromosomes. RNA polymerase I (RNA Pol I) transcribes rDNA into pre-ribosomal RNA (47S pre-rRNA). A large number of processing proteins are required for the splicing and processing of pre-rRNA, resulting in the formation of three rRNA species: 28S, 5.8S, and 18S (2). RNA polymerase II (RNA Pol II) transcribes genes that encode ribosomal proteins and ribosome-associated proteins, whereas RNA polymerase III (RNA Pol III) transcribes the 5S rRNA gene. Thus, while synthesis of mature ribosomes necessitates synchronization of all three RNA polymerases, around 200 processing factors, and about 80 ribosomal proteins, transcription of 45S rRNA by RNA Pol I is considered as a rate-limiting and a key step in ribosome biogenesis. In cancer, dysregulated signaling pathways, metabolic reprogramming, and aberrant expression of noncoding RNAs promote RNA Pol I transcription activity, resulting in ribosome biogenesis hyperactivation (3–7).

Evidence has emerged in recent decades regarding the close link between dysregulated ribosome biogenesis and tumorigenesis. For example, oncogenic c-Myc transcription factor increases protein synthesis and promotes translational capacity by modulating the expression of many genes implicated in ribosome biogenesis (8). Conversely, surveillance systems centered on tumor suppressors (e.g., TP53, PTEN, and RB1) have evolved in normal cells to oppose excessive changes in ribosome biosynthesis and halt cell growth (9). While the impacts of ribosome biogenesis on cancer metastasis, treatment resistance, and clinical outcome are not fully understood, in this review, by integrating the most current findings, we present novel insights into the relationship between ribosome biogenesis and cancer metastasis, as well as potential therapeutic approaches.

Historical overview

The first preliminary indications of the importance of ribosome biogenesis dysregulation in cancer came about with the identification of irregular numbers and shape of nucleoli in cancer cells. This feature was adopted by pathologists with AgNOR staining to mark the nucleolus and evolved to become a hallmark of malignant cells, allowing for the appreciation that nucleolar phenotypes are reflective of ribosome biogenesis (10, 11). One of the first indications that defined the interplay between ribosome biogenesis and cell-cycle progression was the discovery that cell proliferation could be blocked by inhibiting ribosome biogenesis (12). This study was followed by research suggesting that ribosome biogenesis might play an important role in neoplastic transformation wherein aberrations of the major tumor suppressor retinoblastoma and p53 pathways stimulated nucleolar function and led to nucleolar enlargement (13).

One of the earliest studies by Williamson and colleagues provided evidence that dysregulated abundance of pre-RNA transcripts correlated with poor prognosis (14). More recently, the importance of rRNA biogenesis in driving malignant phenotypes was evidenced by the observation that in contrast to normal B cells, lymphoma cells demonstrate greater reliance upon elevated rDNA transcription, rendering them exquisitely sensitive to RNA Pol I inhibition (15). This paradigm-shifting evidence altered the perspective on RNA Pol I activity as merely a byproduct of tumorigenesis, to being a major driver. The discovery of somatic mutations in ribosomal proteins in multiple hematologic and solid malignancies added to the affirmation that ribosomal changes are intimately associated with cancer. Human and animal cell models carrying these mutations show defects and abnormalities in ribosome assembly, cell proliferation, and malignant transformation. As research continues to evolve revealing the complexities of ribosome biogenesis, it has become evident that ribosome biogenesis alterations in cancer can stem from a myriad of crucial steps beginning with rDNA transcription through ribosome modifications collectively driving tumor progression and metastasis.

Ribosomal heterogeneity in cancer

Ribosomes were thought for a long time as complex machines with invariable composition. This view was challenged when Mauro and Edelman first suggested that ribosomes can have heterogeneous composition, and this heterogeneity regulates translation and modulates protein synthesis rates (16). Due to the complexity of their composition, heterogeneity in ribosomes can arise from variability in any of their components, e.g., rRNA modifications, rRNA variants, stoichiometry and paralogs of ribosomal proteins, posttranslational modifications, and ribosome-associated proteins. These variabilities in ribosome composition contribute to the generation of “specialized ribosomes” or in the case of cancer, “onco-ribosomes” (17).

Ribosome heterogeneity plays a role in tumorigenesis and cancer progression (18, 19). Parks and colleagues discovered that the number of rDNA copies varied significantly within and between individual humans and also mice. Variant rRNA alleles are selectively expressed in a tissue-specific manner, and contribute to ribosome heterogeneity (20). Most malignancies have paired 5S rDNA amplification and 45S rDNA deletion, which are linked with higher proliferation rates and unregulated expression of nucleolar genes (introduced as “nucleolar activity”). Wang and colleagues proposed that tumor suppressors and oncogenes have a variety of mutational backgrounds that are linked with recurrent alterations in copy number of rDNA in different cancers (21). Appreciably, each of these alterations can result in ribosome heterogeneity.

Altered rRNA modifications have emerged as oncogenic drivers that can trigger tumor initiation or promote cancer progression. Several new advances contributed to solidifying the importance of altered rRNA modifications in cancer. Noteworthy among this is the report by Marcel and colleagues about the first rRNA 2′-O methylation landscape in primary human breast tumors (22). These efforts uncovered that rRNA 2′-O methylation exhibits intra- and inter-patient variability in breast tumors and is differentially associated with breast cancer subtype and tumor grade (22). Concurrent with this report, using an example of a site in the small ribosomal subunit (SSU-C1440) that is linked to diffuse large B-cell lymphoma pathogenesis, Krogh and colleagues demonstrated a novel concept that sites of rRNA hypomethylation can be used as potential drug targets (23). Metge and colleagues identified that when cancer cells are exposed to stress, e.g., hypoxia, rRNAs acquire distinct methylation patterns and create a subgroup of specialized ribosomes that are capable of performing internal ribosome entry site (IRES)–mediated translation (24). Altered expression of small nucleolar RNAs (snoRNA) accounts for further ribosome heterogeneity, impacting physiologic and pathologic cellular processes, including carcinogenesis (25, 26). rRNAs undergo extensive posttranscriptional modifications, predominantly pseudouridylation (ψ) and ribose 2′-O methylation (2′-O-Me), which are guided by snoRNAs and mediated by box H/ACA and box C/D ribonucleoprotein complexes, respectively (27). Moreover, the rRNA 2′-O-Me landscape is remarkably altered in breast cancer and varies within and across patients’ tumor samples, tumor stage, and subtype (22). For example, SNORD42A, a snoRNA responsible for 2′-O-Me of the uridine116 residue in 18S rRNA, is highly expressed in individuals with acute myeloid leukemia (AML). Elevated abundance of SNORD42A is linked to AML cell proliferation and survival; deleting SNORD42A reduced cellular growth and global protein synthesis (28). In noncancerous cells, p53 regulates the expression of fibrillarin (FBL), a central rRNA methyl transferase. Mutations or alterations in p53 remove the check on FBL, altering the 2′-O-Me marks on ribosomes, resulting in reduced translational fidelity and enhanced IRES-dependent translation. Unchecked FBL activity facilitates tumorigenesis and is associated with an unfavorable prognosis in patients with breast cancer (29).

Another layer of complexity is imparted by heterogeneity of ribosomal proteins – while dysregulated ribosomal protein composition is associated with poor prognosis and worse clinical outcome, it's still somewhat enigmatic what functional relevance there is to this heterogeneity or whether ribosomal protein-dependent regulatory pathways are at work under the surface.

Heterogeneous compositions confer specialized functions to ribosomes, facilitating preferential translation of certain mRNAs in normal and pathologic contexts. In cancer, mutations in ribosomal proteins have been proposed to alter the preferential translation of certain mRNAs, creating a pro-oncogenic proteome promoting cancer progression (30, 31). The term “onco-ribosomes” was coined to describe a form of specialized ribosomes in cancer cells that confer preferential translation of oncogenic and prosurvival genes, facilitating cancer progression (19, 32). Babaian and colleagues identified a cancer-specific single-nucleotide variation in 18S rRNA at nucleotide 1248.U in more than 45% of patients with colorectal cancer. This results in hyper-modification on 18S rRNA at the peptidyl decoding site of the ribosome. A subset of patients with colorectal cancer with hypo-modification is characterized by highly abundant ribosomal proteins that generate heterogeneous onco-ribosomes (33).

The ability of ribosomes to translate efficiently while maintaining high fidelity is critical for cell survival and proliferation. Mutations in ribosomal proteins impact the translational capacity of cells by modulating the rate and fidelity of protein synthesis. Most cell model systems engineered for mutations in ribosomal proteins show permuted translational rate and accuracy. For example, in chronic lymphocytic leukemia (CLL), mutations in the RPS15 gene result in defective ribosomes, impacting the rate and fidelity of protein synthesis (34). Thus, ribosomal heterogeneity and specialized onco-ribosomes are important players in promoting cancer progression. Further investigations are warranted to fully characterize their compositions for therapeutic purposes.

Ribosomopathies and cancer

Ribosomopathies are a group of developmental disorders caused by abnormal ribosome synthesis and dysfunctional ribosomes. Patients with ribosomopathies have a greater risk of developing malignancy later in life (32, 35, 36). By modulating oncogenic signaling pathways and remodeling the translational programs in cancer cells, several studies have highlighted the close connection between mutations in ribosomal proteins and carcinogenesis (18, 36–38). Diamond–Blackfan anemia is caused by mutations in the ribosomal protein genes RPS19, RPL5, RPS26, and RPL11 – these mutations disrupt the translational machinery and are also linked to an elevated risk of malignancies such as leukemia and sarcoma (39). The 5q minus syndrome, which has its etiology in the loss of RPS14 coupled with deletion of the long arm of chromosome 5, is associated with a high risk of developing myelodysplastic syndrome (MDS) and AML (40). Mutations or deletions in RMRP (RNA component of mitochondrial RNA processing endoribonuclease), a pre-rRNA processing factor, cause cartilage-hair hypoplasia-anauxetic dysplasia, a ribosomopathy that is linked to an increased risk of developing non-Hodgkin's lymphoma and basal cell carcinoma (41). Mutations in either DKC1 (Dyskerin pseudouridine synthase 1) or NPM1 (nucleophosmin 1) that impact rRNA pseudouridylation and 2-O'Me, respectively, can lead to dyskeratosis congenita, which is associated with an increased risk of MDS, leukemia, and head and neck malignancies (42, 43). In Table 1, we have presented an organized compilation of mutations in ribosomal proteins and their roles in different cancer types and clinical outcomes (34, 44–75).

Table 1.

Dysregulations in ribosomal proteins are associated with tumor progression and therapeutic resistance.

Ribosomal proteinExpression level/statusCancer typePhenotypeReferences
Ribosomal proteins in tumorigenesis and metastasis 
 RPL5 Mutated (missense) T-ALL, melanoma, and GBM RPL5 mutations dysregulated the HDM2/p53-mediated ribosome biogenesis checkpoint with subsequent dysregulation in ribosome biogenesis 44–46  
 RPL10 Mutated (missense) T-ALL 
  • RPL10 R98S mutant leukemia cells showed a ribosome biogenesis defect.

  • RPL10 R98S mutant leukemia cells showed enhanced IRES-mediated translation and high tolerance to high oxidative stress levels

 
45, 47–49  
 RPL15 Upregulated Colon cancer Silencing of RPL15 inhibited cell proliferation and induced apoptosis 50  
 Upregulated Gastric cancer Knockdown of RPL13 inhibited cell proliferation, migration, and tumor growth in vivo 51  
 RPL19 Upregulated Prostate cancer 
  • Increased RPL19 expression was predictive of shorter patient survival.

  • Silencing RPL19 suppressed tumor growth in vivo.

 
52, 53  
 Upregulated Hepatocellular carcinoma Overexpression of RPL19 predicted poor prognosis. 54  
 RPL22 Downregulated Lung cancer (NSCLC) Downregulation of RPL22 is associated with carcinogenesis. 55  
 Deletions T-ALL Haploinsufficiency or monoallelic loss of RPL22 accelerated development of T-ALL. 56  
 RPL23 Upregulated MDS 
  • Silencing RPL23 suppressed cell proliferation and increased apoptosis.

  • RPL23 overexpression was associated with apoptotic resistance and higher risk of MDS

 
57  
 Upregulated High-grade serous ovarian carcinoma Higher RPL23 mRNA levels were associated with worse prognoses. 58  
 RPL26 Upregulated Pancreatic cancer Knockdown of RPL26 suppressed cell proliferation. 59  
 RPL29 Upregulated Pancreatic cancer Knockdown of RPL29 suppressed cell proliferation. 59  
 RPL34 Upregulated Glioma Knockdown of RPL34 suppressed proliferation and migration of glioma cells. 60  
 Upregulated NSCLC Knockdown of RPL34 suppressed cell proliferation and enhanced apoptosis in NSCLC cell lines. 61  
 Upregulated Osteosarcoma 
  • High levels of RPL34 are associated with poor prognosis for patients with osteosarcoma.

  • Knockdown of RPL34 inhibited cell proliferation, induced cell apoptosis.

 
62  
 Upregulated Oral squamous cell carcinoma Knockdown of RPL34 inhibited cell proliferation and migration. 63  
 RPL41 Downregulated Retinoblastoma 
  • RPL41 peptide therapy improved sensitivity to carboplatin.

  • RPL41 peptide therapy induced apoptosis and inhibited cell migration.

 
64  
 Downregulated Breast cancer RPL41 downregulation is associated with malignant transformation. 65  
 RPS2 Upregulated Prostate cancer Knockdown of RPS2 suppressed cell proliferation and induced apoptosis in malignant prostate cells. 66  
 Phospho-RPS6 Upregulated Lung cancer High levels of phospho-RPS6 are associated with shorter metastasis-free survival. 67  
 RPS15 Mutated (missense) CLL 
  • RPS15 mutant primary CLL cells showed altered translation efficiency and rewiring of the translational program.

  • Mutant RPS15 caused dysregulation of p53 pathway.

 
34, 68–70  
 RPS15A Upregulated Colorectal cancer High levels of RPS15A are associated with poor prognosis. 71  
 RPS20 Mutated (missense) Colorectal cancer RPS20 mutation was associated with a defect in pre-rRNA maturation. 72, 73  
 RPS20 Upregulated GBM Higher levels of RPS20 are associated with poor prognosis. 74  
 RPS27L Upregulated Colorectal cancer Elevated RPS27L expression in either feces or tissues is associated with better prognosis. 75  
Ribosomal proteins in therapeutic resistance 
 RPL3 Downregulated Lung cancer Overexpression of RPL3 inhibited cell migration and invasion and improved 5-FU efficacy in lung cancer cells. 88  
 RPL6 Upregulated Gastric cancer 
  • Downregulation of RPL6 suppressed cell proliferation.

  • Overexpression of RPL6 promoted multidrug resistance.

 
89, 90  
 RPL13 Upregulated Gastric cancer 
  • Knockdown of RPL13 suppressed cell proliferation.

  • Overexpression of RPL13 promoted chemoresistance.

 
91  
 RPL23 Upregulated Gastric cancer RPL23 overexpression promoted multidrug resistance. 92  
 RPL34 Upregulated Pancreatic cancer Knockdown of RPL34 suppressed cell proliferation, migration, and drug resistance of pancreatic cancer cells. 93  
 RPS6 N/A Gastric cancer RPS6 suppression decreased cell proliferation and tumor growth in lapatinib- and trastuzumab-resistant gastric cancer models. 94  
 RPS3 N/A GBM 
  • In radioresistant GBM cell lines, ring finger protein 138 (RNF138) ubiquitinates RPS3 and promotes its degradation, which suppresses radiation-induced apoptosis and confers radioresistance.

  • Silencing of RPS3 enhanced GBM cell tolerance to irradiation in vitro.

 
95  
 Phospho-RPS3 N/A Lung cancer (NSCLC) In radioresistant NSCLC cells, RPS3 phosphorylation plays a key role in radiation resistance and initiating a prosurvival transcriptional program. 96  
 RPS11 Upregulated GBM 
  • Knockdown of RPS11 impaired apoptosis and led to resistance to etoposide and doxorubicin.

  • Higher levels of RPS11 are associated with poor prognosis.

 
74, 97  
 RPS13 Upregulated Gastric cancer RPS13 promotes cell proliferation and multidrug resistance. 92, 98  
 RPS27A Upregulated CML 
  • Patients with CML-accelerated or blast phase have higher levels of RPS27A compared with chronic phase patients.

  • Knockdown of RPS27A improved therapeutic efficacy of tyrosine kinase inhibitor Imatinib.

 
99  
 RPS27L N/A  Rps27l deficiency sensitized Trp53 +/− mice to irradiation by inhibiting cell proliferation, impairing DNA damage response, and inducing apoptosis. 100  
 RPLP1 N/A HNSCC 
  • Silencing of RPLP1 promoted apoptosis and decreased radioresistance in vitro.

  • Invasive HNSCC showed higher expression levels of RPLP1.

 
101  
Ribosomal proteinExpression level/statusCancer typePhenotypeReferences
Ribosomal proteins in tumorigenesis and metastasis 
 RPL5 Mutated (missense) T-ALL, melanoma, and GBM RPL5 mutations dysregulated the HDM2/p53-mediated ribosome biogenesis checkpoint with subsequent dysregulation in ribosome biogenesis 44–46  
 RPL10 Mutated (missense) T-ALL 
  • RPL10 R98S mutant leukemia cells showed a ribosome biogenesis defect.

  • RPL10 R98S mutant leukemia cells showed enhanced IRES-mediated translation and high tolerance to high oxidative stress levels

 
45, 47–49  
 RPL15 Upregulated Colon cancer Silencing of RPL15 inhibited cell proliferation and induced apoptosis 50  
 Upregulated Gastric cancer Knockdown of RPL13 inhibited cell proliferation, migration, and tumor growth in vivo 51  
 RPL19 Upregulated Prostate cancer 
  • Increased RPL19 expression was predictive of shorter patient survival.

  • Silencing RPL19 suppressed tumor growth in vivo.

 
52, 53  
 Upregulated Hepatocellular carcinoma Overexpression of RPL19 predicted poor prognosis. 54  
 RPL22 Downregulated Lung cancer (NSCLC) Downregulation of RPL22 is associated with carcinogenesis. 55  
 Deletions T-ALL Haploinsufficiency or monoallelic loss of RPL22 accelerated development of T-ALL. 56  
 RPL23 Upregulated MDS 
  • Silencing RPL23 suppressed cell proliferation and increased apoptosis.

  • RPL23 overexpression was associated with apoptotic resistance and higher risk of MDS

 
57  
 Upregulated High-grade serous ovarian carcinoma Higher RPL23 mRNA levels were associated with worse prognoses. 58  
 RPL26 Upregulated Pancreatic cancer Knockdown of RPL26 suppressed cell proliferation. 59  
 RPL29 Upregulated Pancreatic cancer Knockdown of RPL29 suppressed cell proliferation. 59  
 RPL34 Upregulated Glioma Knockdown of RPL34 suppressed proliferation and migration of glioma cells. 60  
 Upregulated NSCLC Knockdown of RPL34 suppressed cell proliferation and enhanced apoptosis in NSCLC cell lines. 61  
 Upregulated Osteosarcoma 
  • High levels of RPL34 are associated with poor prognosis for patients with osteosarcoma.

  • Knockdown of RPL34 inhibited cell proliferation, induced cell apoptosis.

 
62  
 Upregulated Oral squamous cell carcinoma Knockdown of RPL34 inhibited cell proliferation and migration. 63  
 RPL41 Downregulated Retinoblastoma 
  • RPL41 peptide therapy improved sensitivity to carboplatin.

  • RPL41 peptide therapy induced apoptosis and inhibited cell migration.

 
64  
 Downregulated Breast cancer RPL41 downregulation is associated with malignant transformation. 65  
 RPS2 Upregulated Prostate cancer Knockdown of RPS2 suppressed cell proliferation and induced apoptosis in malignant prostate cells. 66  
 Phospho-RPS6 Upregulated Lung cancer High levels of phospho-RPS6 are associated with shorter metastasis-free survival. 67  
 RPS15 Mutated (missense) CLL 
  • RPS15 mutant primary CLL cells showed altered translation efficiency and rewiring of the translational program.

  • Mutant RPS15 caused dysregulation of p53 pathway.

 
34, 68–70  
 RPS15A Upregulated Colorectal cancer High levels of RPS15A are associated with poor prognosis. 71  
 RPS20 Mutated (missense) Colorectal cancer RPS20 mutation was associated with a defect in pre-rRNA maturation. 72, 73  
 RPS20 Upregulated GBM Higher levels of RPS20 are associated with poor prognosis. 74  
 RPS27L Upregulated Colorectal cancer Elevated RPS27L expression in either feces or tissues is associated with better prognosis. 75  
Ribosomal proteins in therapeutic resistance 
 RPL3 Downregulated Lung cancer Overexpression of RPL3 inhibited cell migration and invasion and improved 5-FU efficacy in lung cancer cells. 88  
 RPL6 Upregulated Gastric cancer 
  • Downregulation of RPL6 suppressed cell proliferation.

  • Overexpression of RPL6 promoted multidrug resistance.

 
89, 90  
 RPL13 Upregulated Gastric cancer 
  • Knockdown of RPL13 suppressed cell proliferation.

  • Overexpression of RPL13 promoted chemoresistance.

 
91  
 RPL23 Upregulated Gastric cancer RPL23 overexpression promoted multidrug resistance. 92  
 RPL34 Upregulated Pancreatic cancer Knockdown of RPL34 suppressed cell proliferation, migration, and drug resistance of pancreatic cancer cells. 93  
 RPS6 N/A Gastric cancer RPS6 suppression decreased cell proliferation and tumor growth in lapatinib- and trastuzumab-resistant gastric cancer models. 94  
 RPS3 N/A GBM 
  • In radioresistant GBM cell lines, ring finger protein 138 (RNF138) ubiquitinates RPS3 and promotes its degradation, which suppresses radiation-induced apoptosis and confers radioresistance.

  • Silencing of RPS3 enhanced GBM cell tolerance to irradiation in vitro.

 
95  
 Phospho-RPS3 N/A Lung cancer (NSCLC) In radioresistant NSCLC cells, RPS3 phosphorylation plays a key role in radiation resistance and initiating a prosurvival transcriptional program. 96  
 RPS11 Upregulated GBM 
  • Knockdown of RPS11 impaired apoptosis and led to resistance to etoposide and doxorubicin.

  • Higher levels of RPS11 are associated with poor prognosis.

 
74, 97  
 RPS13 Upregulated Gastric cancer RPS13 promotes cell proliferation and multidrug resistance. 92, 98  
 RPS27A Upregulated CML 
  • Patients with CML-accelerated or blast phase have higher levels of RPS27A compared with chronic phase patients.

  • Knockdown of RPS27A improved therapeutic efficacy of tyrosine kinase inhibitor Imatinib.

 
99  
 RPS27L N/A  Rps27l deficiency sensitized Trp53 +/− mice to irradiation by inhibiting cell proliferation, impairing DNA damage response, and inducing apoptosis. 100  
 RPLP1 N/A HNSCC 
  • Silencing of RPLP1 promoted apoptosis and decreased radioresistance in vitro.

  • Invasive HNSCC showed higher expression levels of RPLP1.

 
101  

Abbreviations: CML, chronic myeloid leukemia; GBM, glioblastoma; HNSCC, head and neck squamous cell carcinoma; N/A, information on clinical expression is not available; NSCLC, non–small cell lung carcinoma; T-ALL, T-cell acute lymphoblastic leukemia.

Ribosome biogenesis in metastasis

Metastatic colonization of cancer cells requires a precisely orchestrated series of events that allow cells to escape the primary tumor and invade at the metastatic site. One of the well-studied events during this process is epithelial-to-mesenchymal transition (EMT). EMT is a critical evolutionary conserved program that defines a vital process that orchestrates morphogenesis and organogenesis (76, 77), and is recapitulated during cancer progression (76–79). Ribosome biogenesis is an important event for metabolically active cells, and it is logical that increased ribosome biogenesis may be essential for executing metabolic plasticity needed for the EMT program. Micalizzi and colleagues (80) elegantly reviewed the impact of the EMT program on translation and translational regulation during metastasis. However, the impacts of ribosome biogenesis and rRNA transcription extend far beyond the bookends of the translation process.

The link between EMT, ribosome biogenesis, and rRNA transcriptional regulation remains tenuous, though emerging reports have begun to bridge an important interplay between these processes. Initial indications of the influence of EMT on ribosome biogenesis came from Wnt5a treatment of MCF7 breast cancer cells, in which Wnt5a repressed rDNA transcription via localization of Disheveled 1 to rDNA (81). In this context, Wnt5a suppression of rDNA transcription aligned with known functions of Wnt5a in breast cancer to reduce migration and invasion. A hallmark study by Prakash and colleagues, concisely detailed an association between initiation of the EMT program concomitant with activation of rDNA transcription. Induction of EMT led to enhanced rRNA synthesis aligned with classical features of mesenchymal phenotypes, timed with the onset of the EMT program. Inhibition of rRNA synthesis shifted the EMT program and reduced metastasis (82). On the other hand, in MCF7 cells, incorporation of exogenously provided ribosomes induced EMT, accompanied by transdifferention in subtype marked by ERα suppression (83). Such shifts in tumor subtypes as a result of modulating rDNA transcription give way to the possibility that certain combination therapies may become effective in these tumors because of broad phenotypic changes incurred through impaired ribosome biogenesis.

Epigenetic regulation of rDNA transcription is an important regulatory node of ribosome biogenesis, and NoRC (nucleolar remodeling complex) maintains the silent states of rDNA clusters. Epigenetic regulation of EMT is well documented; however, recent work has linked epigenetic modulation of rDNA to increased invasion and migration. EZH2, the enzymatic catalytic subunit of polycomb repressive complex 2 (PRC2), is a major epigenetic writer that influences various aspects of tumor progression. Most recently, EZH2 was found to regulate long noncoding RNA (lncRNA) responsible for methylation of rDNA loci, thereby suppressing ribosome biogenesis, suggesting that the interplay between epigenetic regulation of rDNA with EMT may prime cancer cell metastasis (84).

Ribosome biogenesis is dependent on RNA Pol I transcriptional activity and incorporation of a myriad of ribosomal associated proteins that significantly impact ribosome function. A number of recent studies have demonstrated the importance of ribosomal proteins influencing tumor progression and metastasis. Ebright and colleagues identified a subset of ribosome gene signatures in breast cancer circulating tumor cells (CTC) that were crucial in predicting poor clinical outcomes. RPL15 was identified as a critical driver of increased metastasis in CTCs; importantly, RPL15 overexpression promotes translation of core ribosomal proteins and drives global translation, implying the impact of ribosomal proteins on dictating metastatic potential of cancer cells (85). Single-cell RNA sequencing also identified increased RPL15 and RPL27A in triple-negative breast cancer; moreover, RPL27A silencing diminished migration and invasion in breast cancer cells (86). Underscoring the importance of ribosomal proteins in EMT-induced ribosome biogenesis, was a recent finding reporting that La-related protein 6 (LARP6) upregulation during EMT drives localization of ribosomal proteins in migrating cells (87). LARP6 induction was found to mediate re-localization of ribosomal proteins to protrusive cell fronts, thereby enhancing ribosome biogenesis and allowing for preferential translation of mRNA subsets that exacerbate metastatic potential. This work lends further support to the importance of ribosomal associated proteins, and highlights changes in ribosomal protein content, as influenced by EMT, as an important regulatory step in transitioning cancer cells to highly migratory and invasive states.

Overall, growing evidence has strongly identified an important link between the EMT program and ribosome biogenesis, which culminates in enhanced migration, invasion, and ultimately metastasis. Collectively, current studies demonstrate not only the importance of rRNA transcriptional regulation, but also highlight epigenetic modifications and ribosome associated proteins as important factors that allow cancer cells to manipulate cellular programs such as EMT, thereby promoting metastatic potential. Ultimately, therapies aimed at targeting ribosome biogenesis induced during EMT may be a viable approach for a subset of patients. Clearly, more in-depth studies are needed to unravel the complexities linking EMT and ribosome biogenesis.

Ribosome biogenesis in therapeutic resistance

Despite anticancer treatments, cancer cells have the capacity to survive and become resistant to chemotherapy and radiation, resulting in a poor clinical outcome. Several studies have demonstrated that proteins involved in ribosome biogenesis mediate radioresistance and chemoresistance in cancer models. Highlighting the importance of ribosome biogenesis in therapy resistance, Table 1 details a number of ribosomal proteins that modulate therapeutic resistance in various cancers (74, 88–101). In addition to ribosomal proteins, rRNA processing, rRNA modifying, and assembly proteins involved in ribosome biogenesis may have important roles in therapeutic resistance. Inactivation of the 60S subunit assembly factor, Bop1, provides cancer cells with a survival advantage to resist high-dose chemotherapy (102). Conversely, nucleolin, a protein essential for ribosome synthesis and RNA processing, improves glioma stem cell sensitivity to temozolomide, partially by DNA repair regulation (103). The rRNA modifying protein NOP2/Sun RNA Methyltransferase 5 (NSUN5) is a candidate RNA methyltransferase for 5-methylcytosine on 28S rRNA at position C3782. Its loss spurs an adaptive translational program that enables tumor cell survival in conditions of stress but paradoxically is associated with a favorable clinical outcome (104). Similarly, rRNA and rDNA processing proteins influence radiation resistance in different cancer models. As an example, rRNA processing protein NOB1 is involved in radioresistance; its knockdown reduced cell proliferation, suppressed apoptosis, and increased the radiosensitivity in in vitro and in vivo models of papillary thyroid carcinoma (105). As such, apart from traditional roles in translation, a complex ensemble of ribosomal proteins and associated ribosome biogenesis factors collectively mediate cancer cell therapeutic response.

For decades, the nucleolus and its related pathways have been shown to exert control over several cellular functions that contribute to tumorigenesis and cancer progression. Thus, RNA Pol I and ribosome biogenesis were thought-provoking targets for cancer therapeutics. The ability to provide therapeutic selectivity for cancer cells and minimize the side effects of cancer therapeutics has been the optimum goal in targeting cancer generally and ribosome biogenesis specifically. Several cancer chemotherapeutic agents such as chemotherapeutic reagents like cisplatin, oxaliplatin, doxorubicin, and mitoxantrone were found to inhibit rRNA transcription and processing (106–110). Oxaliplatin and phenanthriplatin were demonstrated to induce ribosome biogenesis stress and impact pre-rRNA formation without inducing DNA damage, unlike cisplatin. Further investigations determined that oxaliplatin and phenanthriplatin induced cytotoxicity through RPL11, and silencing RPL11 led to resistance to these drugs (107).

Inhibiting RNA Pol I transcription triggers nucleolar stress and results in translocation of ribosomal proteins from the nucleolus to the nucleoplasm, where proteins like RPL5 and RPL11 bind to MDM2, triggering its dissociation and therefore stimulation of p53 (111). Thus, by sustaining high levels of RNA Pol I transcription, cancer cells maintain nucleolar integrity and keep p53 under check (111). Therefore, the concept of inhibiting RNA Pol I for cancer therapeutics attracted investigators to design specific inhibitors to target RNA Pol I, with the expectation that normal cells would be spared because they are much less dependent on RNA Pol I transcription activity than cancer cells.

CX-5461 was the first selective and orally available inhibitor of RNA Pol I transcription (112, 113). CX-5461 acts by perturbing the SL1-rDNA complex, compromising upstream binding transcription factor (UBTF) stabilization, and thus reducing the recruitment of RNA Pol I to the rDNA promoter (113). In preclinical models of melanoma and pancreatic cancer CX-5461 showed significant antitumor activity and induced potent cytotoxicity in cancer cells regardless of their P53 mutation status. CX-5461 was also found to work against hematologic malignancies, for example, in a MYC-induced lymphoma mouse model (11). Inhibition of ATM/ATR in combination with CX-5461 showed improved therapeutic benefit in treating tumors that lack P53 (114, 115). CX-5461 demonstrated clinical efficacy in AML and multiple myeloma (116–118) and showed a promising therapeutic effect in ovarian carcinomas by P53-independent initiation of DNA damage (119, 120). CX-5461 also sensitized homologous recombination (HR)-proficient castration-resistant prostate cancer (CRPC) to the PARP inhibitor talazoparib, synergistically inhibiting tumor growth in a preclinical CRPC PDX model (121).

BMH-21 is another potent small molecule RNA Pol I inhibitor that was discovered by a chemical compound library screen for p53 pathway activation in a human cancer cell line by Laiho and colleagues (122). BMH-21 inhibits RNA Pol I transcription by proteasome-dependent degradation of RPA194, the large catalytic protein subunit of RNA Pol I holocomplex, resulting in p53 activation (123). While not yet tested in clinical trials, in various preclinical studies BMH21 has shown promising therapeutic efficacy towards different hematologic and solid tumors (124–127). A second generation RNA Pol I inhibitor molecule, PMR-116, demonstrates greater efficacy and improved chemical properties compared with CX-5461. Unlike CX-5461, PMR-116 induces phosphorylation and accumulation of p53 without nonspecifically activating CHK2 (128). Altogether, because ribosome biogenesis is a central process that contributes to cell survival and stress adaptive response, several investigations have explored the prospects of targeting ribosome biogenesis to interfere with the evolution of resistance to radiotherapy and chemotherapy.

Independent of RNA Pol I, the perinucleolar compartment (PNC) has emerged as a promising niche to screen for targeting ribosome biogenesis inhibitors (129). Remarkably, PNC is a phenotypic marker that reflects metastatic capability (130). High PNC prevalence in primary tumors is associated with poor patient outcomes, including overall survival of patients with breast, colorectal, and ovarian cancer (130–132). Using PNC reduction as a surrogate marker, multiple high-content screens were performed and those yielded several lead compounds (129, 133). One such well-described, promising compound is Metarrestin that inhibits Pol I transcription, induces nucleolar segregation, reduces nucleolar volume, and reduces metastasis in an experimental model of prostate cancer (134). Overall, ribosome biogenesis inhibition by RNA Pol I inhibition or disruption of PNC presents a novel therapeutic avenue to overcome the chemotherapeutic resistance in multiple tumor types.

Aberrations in ribosomal proteins are documented in multiple ribosomopathies and cancers. This is suggestive of a potential for monitoring ribosomal proteins in prognosticating chemo/radioresistance of tumor cells. Therefore, it would be useful to investigate the utility of genetic screening of ribosomal proteins in treatment-naïve patients with cancer. The influence of the tumor microenvironment, intratumoral heterogeneity, and ribosome heterogeneity are all new, unexplored fields. Stressors like intratumoral hypoxia and acidosis can create tumor regions with differential activation of ribosome biogenesis, which may confer irregular therapeutic responsiveness and a selective pressure for cancer evolution toward more aggressive and treatment-resistant phenotypes. Furthermore, identifying translational changes linked to metastasis may lead to new therapy targets, particularly at critical points in the metastatic cascade where there is a higher dependence on translating a new set of mRNAs (135, 136).

Nucleolar integrity and rRNA transcription are maintained by RNA Pol II–mediated transcription of Alu elements (alu RNAs). Since alu RNAs are localized in the nucleoli and interact with NPM1 and nucleolin, rRNA biogenesis and nucleolar architecture are disrupted when expression of alu RNAs is altered (137). In addition, Abraham and colleagues, uncovered that nucleolar RNA Pol II plays an essential role in promoting rRNA and ribosome biogenesis by binding to rDNA-flanking regions and forming R-loops. As a consequence, RNA Pol I–mediated transcription of sense intergenic noncoding RNAs (sincRNA) is inhibited preserving the nucleolar architecture and maintaining rRNA transcription (138). While it is speculated that increased level of sincRNAs may lead to aberrant nucleolar morphology seen in cancer, these findings open the doors to further investigations into the noncanonical roles of RNA polymerases and novel potential regulators of ribosome biogenesis in physiologic and pathologic contexts. In addition, several lncRNA species, e.g., promoter-associated RNAs (pRNA), pyrimidine-rich noncoding transcript (PNCTR), promoter and pre-rRNA antisense (PAPAS), regulate RNA Pol I transcription and rRNA biogenesis, yet their relevance in cancer is understudied (139–141)

Another unexplored area is the impact of malignant cell transformation on the liquid/liquid phase separation of nucleoli (nucleolar dynamics). It was shown that the NORs can undergo prominent changes in response to chemical or environmental stress. However, to date no comprehensive studies have been conducted to establish if NORs are altered in cancer cells and whether these changes are cancer-type specific. Besides, little is known about the impact of aneuploidy in cancer cells on the nucleolar dynamics – specifically if aneuploidy alters rRNA and ribosome biogenesis, ultimately impacting cellular response to RNA Pol I inhibitors.

Advances in rRNA epitranscriptomics in the context of tumor growth and metastasis present several promising prospects. These rRNA epitranscriptomic modifications may potentially be important diagnostic markers or may help patient stratification. The molecular machinery responsible for these marks bears promise as novel drug targets. Specifically, differential snoRNA expression and differential rRNA 2'-O methylation in various cancers offer new opportunities for cancer prognostics and therapeutics. These will become a reality following controlled studies involving significantly large cohorts of patients. However, because ribosome biogenesis is critical for cell survival, various players in this process may potentially have functional redundancy. In addition, diverse tumor cell populations due to intratumoral variability contributes to complexity of ribosomal heterogeneity. Thus, it is challenging to define a unique event to target ribosome biogenesis of all the cells in a tumor. However, as a combination treatment, ribosome biogenesis inhibition may offer a logical way to make tumor cells vulnerable to classical cytotoxic chemotherapy. As such, it is evident that additional investigations are necessary to mechanistically understand the significance of ribosome biogenesis in the context of tumor formation, progression, metastasis, and therapeutic resistance.

L.A. Shevde reports grants from O'Neal Invests during the conduct of the study. No disclosures were reported by the other authors.

The work is supported in part by I01 BX003374 (VA), CA194048 (NCI/NIH), and O'Neal Invests Award (to R.S. Samant); Department of Defense (W81XWH-18-1-0036 and W81XWH-10-1-0755) and O'Neal Invests Award (to L.A. Shevde).

1.
Uniacke
J
,
Perera
JK
,
Lachance
G
,
Francisco
CB
,
Lee
S
.
Cancer cells exploit eIF4E2-directed synthesis of hypoxia response proteins to drive tumor progression
.
Cancer Res
2014
;
74
:
1379
89
.
2.
Pelletier
J
,
Thomas
G
,
Volarevic
S
.
Ribosome biogenesis in cancer: new players and therapeutic avenues
.
Nat Rev Cancer
2018
;
18
:
51
63
.
3.
Drygin
D
,
Rice
WG
,
Grummt
I
.
The RNA polymerase I transcription machinery: an emerging target for the treatment of cancer
.
Annu Rev Pharmacol Toxicol
2010
;
50
:
131
56
.
4.
Ferreira
R
,
Schneekloth
JS
Jr
,
Panov
KI
,
Hannan
KM
,
Hannan
RD
.
Targeting the RNA polymerase I transcription for cancer therapy comes of age
.
Cells
2020
;
9
:
266
.
5.
Schneider
DA
.
RNA polymerase I activity is regulated at multiple steps in the transcription cycle: recent insights into factors that influence transcription elongation
.
Gene
2012
;
493
:
176
84
.
6.
McCool
MA
,
Bryant
CJ
,
Baserga
SJ
.
MicroRNAs and long noncoding RNAs as novel regulators of ribosome biogenesis
.
Biochem Soc Trans
2020
;
48
:
595
612
.
7.
Donati
G
,
Montanaro
L
,
Derenzini
M
.
Ribosome biogenesis and control of cell proliferation: p53 is not alone
.
Cancer Res
2012
;
72
:
1602
7
.
8.
van Riggelen
J
,
Yetil
A
,
Felsher
DW
.
MYC as a regulator of ribosome biogenesis and protein synthesis
.
Nat Rev Cancer
2010
;
10
:
301
9
.
9.
Zhai
W
,
Comai
L
.
Repression of RNA polymerase I transcription by the tumor suppressor p53
.
Mol Cell Biol
2000
;
20
:
5930
8
.
10.
Derenzini
M
,
Farabegoli
F
,
Trere
D
.
Relationship between interphase AgNOR distribution and nucleolar size in cancer cells
.
Histochem J
1992
;
24
:
951
6
.
11.
Derenzini
M
,
Trere
D
,
Pession
A
,
Montanaro
L
,
Sirri
V
,
Ochs
RL
.
Nucleolar function and size in cancer cells
.
Am J Pathol
1998
;
152
:
1291
7
.
12.
Volarevic
S
,
Stewart
MJ
,
Ledermann
B
,
Zilberman
F
,
Terracciano
L
,
Montini
E
, et al
.
Proliferation, but not growth, blocked by conditional deletion of 40S ribosomal protein S6
.
Science
2000
;
288
:
2045
7
.
13.
Derenzini
M
,
Montanaro
L
,
Trere
D
.
What the nucleolus says to a tumor pathologist
.
Histopathology
2009
;
54
:
753
62
.
14.
Williamson
D
,
Lu
YJ
,
Fang
C
,
Pritchard-Jones
K
,
Shipley
J
.
Nascent pre-rRNA overexpression correlates with an adverse prognosis in alveolar rhabdomyosarcoma
.
Genes Chromosomes Cancer
2006
;
45
:
839
45
.
15.
Bywater
MJ
,
Poortinga
G
,
Sanij
E
,
Hein
N
,
Peck
A
,
Cullinane
C
, et al
.
Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53
.
Cancer Cell
2012
;
22
:
51
65
.
16.
Mauro
VP
,
Edelman
GM
.
The ribosome filter hypothesis
.
Proc Natl Acad Sci USA
2002
;
99
:
12031
6
.
17.
Li
D
,
Wang
J
.
Ribosome heterogeneity in stem cells and development
.
J Cell Biol
2020
;
219
:
e202001108
.
18.
Sulima
SO
,
Hofman
IJF
,
De Keersmaecker
K
,
Dinman
JD
.
How ribosomes translate cancer
.
Cancer Discov
2017
;
7
:
1069
87
.
19.
Bastide
A
,
David
A
.
The ribosome, (slow) beating heart of cancer (stem) cell
.
Oncogenesis
2018
;
7
:
34
.
20.
Parks
MM
,
Kurylo
CM
,
Dass
RA
,
Bojmar
L
,
Lyden
D
,
Vincent
CT
, et al
.
Variant ribosomal RNA alleles are conserved and exhibit tissue-specific expression
.
Sci Adv
2018
;
4
:
eaao0665
.
21.
Wang
M
,
Lemos
B
.
Ribosomal DNA copy-number amplification and loss in human cancers is linked to tumor genetic context, nucleolus activity, and proliferation
.
PLoS Genet
2017
;
13
:
e1006994
.
22.
Marcel
V
,
Kielbassa
J
,
Marchand
V
,
Natchiar
KS
,
Paraqindes
H
,
Nguyen Van Long
F
, et al
.
Ribosomal RNA 2'O-methylation as a novel layer of inter-tumor heterogeneity in breast cancer
.
NAR Cancer
2020
;
2
:
zcaa036
.
23.
Krogh
N
,
Asmar
F
,
Come
C
,
Munch-Petersen
HF
,
Gronbaek
K
,
Nielsen
H
.
Profiling of ribose methylations in ribosomal RNA from diffuse large B-cell lymphoma patients for evaluation of ribosomes as drug targets
.
NAR Cancer
2020
;
2
:
zcaa035
.
24.
Metge
BJ
,
Kammerud
SC
,
Pruitt
HC
,
Shevde
LA
,
Samant
RS
.
Hypoxia re-programs 2'-O-Me modifications on ribosomal RNA
.
iScience
2021
;
24
:
102010
.
25.
Lafontaine
DL
.
Noncoding RNAs in eukaryotic ribosome biogenesis and function
.
Nat Struct Mol Biol
2015
;
22
:
11
9
.
26.
Gay
DM
,
Lund
AH
,
Jansson
MD
.
Translational control through ribosome heterogeneity and functional specialization
.
Trends Biochem Sci
2021
;
47
:
66
81
.
27.
Sloan
KE
,
Warda
AS
,
Sharma
S
,
Entian
KD
,
Lafontaine
DLJ
,
Bohnsack
MT
.
Tuning the ribosome: the influence of rRNA modification on eukaryotic ribosome biogenesis and function
.
RNA Biol
2017
;
14
:
1138
52
.
28.
Pauli
C
,
Liu
Y
,
Rohde
C
,
Cui
C
,
Fijalkowska
D
,
Gerloff
D
, et al
.
Site-specific methylation of 18S ribosomal RNA by SNORD42A is required for acute myeloid leukemia cell proliferation
.
Blood
2020
;
135
:
2059
70
.
29.
Marcel
V
,
Ghayad
SE
,
Belin
S
,
Therizols
G
,
Morel
AP
,
Solano-Gonzalez
E
, et al
.
p53 acts as a safeguard of translational control by regulating fibrillarin and rRNA methylation in cancer
.
Cancer Cell
2013
;
24
:
318
30
.
30.
Guimaraes
JC
,
Zavolan
M
.
Patterns of ribosomal protein expression specify normal and malignant human cells
.
Genome Biol
2016
;
17
:
236
.
31.
Genuth
NR
,
Barna
M
.
The discovery of ribosome heterogeneity and its implications for gene regulation and organismal life
.
Mol Cell
2018
;
71
:
364
74
.
32.
Kampen
KR
,
Sulima
SO
,
Vereecke
S
,
De Keersmaecker
K
.
Hallmarks of ribosomopathies
.
Nucleic Acids Res
2020
;
48
:
1013
28
.
33.
Babaian
A
,
Rothe
K
,
Girodat
D
,
Minia
I
,
Djondovic
S
,
Milek
M
, et al
.
Loss of m1 acp3 ψ ribosomal RNA modification is a major feature of Cancer
.
Cell Rep
2020
;
31
:
107611
.
34.
Bretones
G
,
Alvarez
MG
,
Arango
JR
,
Rodriguez
D
,
Nadeu
F
,
Prado
MA
, et al
.
Altered patterns of global protein synthesis and translational fidelity in RPS15-mutated chronic lymphocytic leukemia
.
Blood
2018
;
132
:
2375
88
.
35.
Aspesi
A
,
Ellis
SR
.
Rare ribosomopathies: insights into mechanisms of cancer
.
Nat Rev Cancer
2019
;
19
:
228
38
.
36.
Sulima
SO
,
Kampen
KR
,
De Keersmaecker
K
.
Cancer biogenesis in ribosomopathies
.
Cells
2019
;
8
:
229
.
37.
Farley
KI
,
Baserga
SJ
.
Probing the mechanisms underlying human diseases in making ribosomes
.
Biochem Soc Trans
2016
;
44
:
1035
44
.
38.
Kang
J
,
Brajanovski
N
,
Chan
KT
,
Xuan
J
,
Pearson
RB
,
Sanij
E
.
Ribosomal proteins and human diseases: molecular mechanisms and targeted therapy
.
Signal Transduct Target Ther
2021
;
6
:
323
.
39.
Horos
R
,
Ijspeert
H
,
Pospisilova
D
,
Sendtner
R
,
Andrieu-Soler
C
,
Taskesen
E
, et al
.
Ribosomal deficiencies in Diamond–Blackfan anemia impair translation of transcripts essential for differentiation of murine and human erythroblasts
.
Blood
2012
;
119
:
262
72
.
40.
Lee
JH
,
List
A
,
Sallman
DA
.
Molecular pathogenesis of myelodysplastic syndromes with deletion 5q
.
Eur J Haematol
2019
;
102
:
203
9
.
41.
Makitie
O
,
Vakkilainen
S
.
Cartilage-hair hypoplasia - anauxetic dysplasia spectrum disorders
. In:
Adam
MP
,
Ardinger
HH
,
Pagon
RA
,
Wallace
SE
,
Bean
LJH
,
Mirzaa
G
, et al
.,
editors
.
GeneReviews
[Internet]. Seattle (WA): University of Washington, Seattle; 1993–2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1116/.
42.
AlSabbagh
MM
.
Dyskeratosis congenita: a literature review
.
J Dtsch Dermatol Ges
2020
;
18
:
943
67
.
43.
Nachmani
D
,
Bothmer
AH
,
Grisendi
S
,
Mele
A
,
Bothmer
D
,
Lee
JD
, et al
.
Germline NPM1 mutations lead to altered rRNA 2'-O-methylation and cause dyskeratosis congenita
.
Nat Genet
2019
;
51
:
1518
29
.
44.
Orsolic
I
,
Bursac
S
,
Jurada
D
,
Hofman
ID
,
Dembic
Z
,
Bartek
J
, et al
.
Cancer-associated mutations in the ribosomal protein L5 gene dysregulate the HDM2/p53-mediated ribosome biogenesis checkpoint
.
Oncogene
2020
;
39
:
3443
57
.
45.
De Keersmaecker
K
,
Atak
ZK
,
Li
N
,
Vicente
C
,
Patchett
S
,
Girardi
T
, et al
.
Exome sequencing identifies mutation in CNOT3 and ribosomal genes RPL5 and RPL10 in T-cell acute lymphoblastic leukemia
.
Nat Genet
2013
;
45
:
186
90
.
46.
Lawrence
MS
,
Stojanov
P
,
Mermel
CH
,
Robinson
JT
,
Garraway
LA
,
Golub
TR
, et al
.
Discovery and saturation analysis of cancer genes across 21 tumor types
.
Nature
2014
;
505
:
495
501
.
47.
Kampen
KR
,
Sulima
SO
,
Verbelen
B
,
Girardi
T
,
Vereecke
S
,
Rinaldi
G
, et al
.
The ribosomal RPL10 R98S mutation drives IRES-dependent BCL-2 translation in T-ALL
.
Leukemia
2019
;
33
:
319
32
.
48.
Girardi
T
,
Vereecke
S
,
Sulima
SO
,
Khan
Y
,
Fancello
L
,
Briggs
JW
, et al
.
The T-cell leukemia-associated ribosomal RPL10 R98S mutation enhances JAK-STAT signaling
.
Leukemia
2018
;
32
:
809
19
.
49.
Abdelfattah
N
,
Rajamanickam
S
,
Panneerdoss
S
,
Timilsina
S
,
Yadav
P
,
Onyeagucha
BC
, et al
.
MiR-584–5p potentiates vincristine and radiation response by inducing spindle defects and DNA damage in medulloblastoma
.
Nat Commun
2018
;
9
:
4541
.
50.
Dong
Z
,
Jiang
H
,
Liang
S
,
Wang
Y
,
Jiang
W
,
Zhu
C
.
Ribosomal protein L15 is involved in colon carcinogenesis
.
Int J Med Sci
2019
;
16
:
1132
41
.
51.
Wang
H
,
Zhao
LN
,
Li
KZ
,
Ling
R
,
Li
XJ
,
Wang
L
.
Overexpression of ribosomal protein L15 is associated with cell proliferation in gastric cancer
.
BMC Cancer
2006
;
6
:
91
.
52.
Bee
A
,
Ke
Y
,
Forootan
S
,
Lin
K
,
Beesley
C
,
Forrest
SE
, et al
.
Ribosomal protein l19 is a prognostic marker for human prostate cancer
.
Clin Cancer Res
2006
;
12
:
2061
5
.
53.
Bee
A
,
Brewer
D
,
Beesley
C
,
Dodson
A
,
Forootan
S
,
Dickinson
T
, et al
.
siRNA knockdown of ribosomal protein gene RPL19 abrogates the aggressive phenotype of human prostate cancer
.
PLoS One
2011
;
6
:
e22672
.
54.
Rao
B
,
Li
J
,
Ren
T
,
Yang
J
,
Zhang
G
,
Liu
L
, et al
.
RPL19 is a prognostic biomarker and promotes tumor progression in hepatocellular carcinoma
.
Front Cell Dev Biol
2021
;
9
:
686547
.
55.
Yang
M
,
Sun
H
,
Wang
H
,
Zhang
S
,
Yu
X
,
Zhang
L
.
Downregulation of ribosomal protein L22 in non–small cell lung cancer
.
Med Oncol
2013
;
30
:
646
.
56.
Rao
S
,
Lee
SY
,
Gutierrez
A
,
Perrigoue
J
,
Thapa
RJ
,
Tu
Z
, et al
.
Inactivation of ribosomal protein L22 promotes transformation by induction of the stemness factor, Lin28B
.
Blood
2012
;
120
:
3764
73
.
57.
Qi
Y
,
Li
X
,
Chang
C
,
Xu
F
,
He
Q
,
Zhao
Y
, et al
.
Ribosomal protein L23 negatively regulates cellular apoptosis via the RPL23/Miz-1/c-Myc circuit in higher-risk myelodysplastic syndrome
.
Sci Rep
2017
;
7
:
2323
.
58.
Kang
H
,
Choi
MC
,
Kim
S
,
Jeong
JY
,
Kwon
AY
,
Kim
TH
, et al
.
USP19 and RPL23 as candidate prognostic markers for advanced-stage high-grade serous ovarian carcinoma
.
Cancers
2021
;
13
:
3976
.
59.
Li
C
,
Ge
M
,
Yin
Y
,
Luo
M
,
Chen
D
.
Silencing expression of ribosomal protein L26 and L29 by RNA interfering inhibits proliferation of human pancreatic cancer PANC-1 cells
.
Mol Cell Biochem
2012
;
370
:
127
39
.
60.
Ji
P
,
Wang
L
,
Liu
J
,
Mao
P
,
Li
R
,
Jiang
H
, et al
.
Knockdown of RPL34 inhibits the proliferation and migration of glioma cells through the inactivation of JAK/STAT3 signaling pathway
.
J Cell Biochem
2019
;
120
:
3259
67
.
61.
Yang
S
,
Cui
J
,
Yang
Y
,
Liu
Z
,
Yan
H
,
Tang
C
, et al
.
Overexpressed RPL34 promotes malignant proliferation of non–small cell lung cancer cells
.
Gene
2016
;
576
:
421
8
.
62.
Luo
S
,
Zhao
J
,
Fowdur
M
,
Wang
K
,
Jiang
T
,
He
M
.
Highly expressed ribosomal protein L34 indicates poor prognosis in osteosarcoma and its knockdown suppresses osteosarcoma proliferation probably through translational control
.
Sci Rep
2016
;
6
:
37690
.
63.
Dai
J
,
Wei
W
.
Influence of the RPL34 gene on the growth and metastasis of oral squamous cell carcinoma cells
.
Arch Oral Biol
2017
;
83
:
40
6
.
64.
Geng
W
,
Ren
J
,
Shi
H
,
Qin
F
,
Xu
X
,
Xiao
S
, et al
.
RPL41 sensitizes retinoblastoma cells to chemotherapeutic drugs via ATF4 degradation
.
J Cell Physiol
2021
;
236
:
2214
25
.
65.
Wang
S
,
Huang
J
,
He
J
,
Wang
A
,
Xu
S
,
Huang
SF
, et al
.
RPL41, a small ribosomal peptide deregulated in tumors, is essential for mitosis and centrosome integrity
.
Neoplasia
2010
;
12
:
284
93
.
66.
Wang
M
,
Hu
Y
,
Stearns
ME
.
RPS2: a novel therapeutic target in prostate cancer
.
J Exp Clin Cancer Res
2009
;
28
:
6
.
67.
McDonald
JM
,
Pelloski
CE
,
Ledoux
A
,
Sun
M
,
Raso
G
,
Komaki
R
, et al
.
Elevated phospho-S6 expression is associated with metastasis in adenocarcinoma of the lung
.
Clin Cancer Res
2008
;
14
:
7832
7
.
68.
Landau
DA
,
Tausch
E
,
Taylor-Weiner
AN
,
Stewart
C
,
Reiter
JG
,
Bahlo
J
, et al
.
Mutations driving CLL and their evolution in progression and relapse
.
Nature
2015
;
526
:
525
30
.
69.
Ljungstrom
V
,
Cortese
D
,
Young
E
,
Pandzic
T
,
Mansouri
L
,
Plevova
K
, et al
.
Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations
.
Blood
2016
;
127
:
1007
16
.
70.
Ntoufa
S
,
Gerousi
M
,
Laidou
S
,
Psomopoulos
F
,
Tsiolas
G
,
Moysiadis
T
, et al
.
RPS15 mutations rewire RNA translation in chronic lymphocytic leukemia
.
Blood Adv
2021
;
5
:
2788
92
.
71.
Chen
J
,
Wei
Y
,
Feng
Q
,
Ren
L
,
He
G
,
Chang
W
, et al
.
Ribosomal protein S15A promotes malignant transformation and predicts poor outcome in colorectal cancer through misregulation of p53 signaling pathway
.
Int J Oncol
2016
;
48
:
1628
38
.
72.
Nieminen
TT
,
O'Donohue
MF
,
Wu
Y
,
Lohi
H
,
Scherer
SW
,
Paterson
AD
, et al
.
Germline mutation of RPS20, encoding a ribosomal protein, causes predisposition to hereditary nonpolyposis colorectal carcinoma without DNA mismatch repair deficiency
.
Gastroenterology
2014
;
147
:
595
8
.
73.
Broderick
P
,
Dobbins
SE
,
Chubb
D
,
Kinnersley
B
,
Dunlop
MG
,
Tomlinson
I
, et al
.
Validation of recently proposed colorectal cancer susceptibility gene variants in an analysis of families and patients: a systematic review
.
Gastroenterology
2017
;
152
:
75
7
.
74.
Yong
WH
,
Shabihkhani
M
,
Telesca
D
,
Yang
S
,
Tso
JL
,
Menjivar
JC
, et al
.
Ribosomal proteins RPS11 and RPS20, two stress-response markers of glioblastoma stem cells, are novel predictors of poor prognosis in glioblastoma patients
.
PLoS One
2015
;
10
:
e0141334
.
75.
Huang
CJ
,
Yang
SH
,
Lee
CL
,
Cheng
YC
,
Tai
SY
,
Chien
CC
.
Ribosomal protein S27-like in colorectal cancer: a candidate for predicting prognoses
.
PLoS One
2013
;
8
:
e67043
.
76.
Aiello
NM
,
Kang
Y
.
Context-dependent EMT programs in cancer metastasis
.
J Exp Med
2019
;
216
:
1016
26
.
77.
Ye
X
,
Weinberg
RA
.
Epithelial–mesenchymal plasticity: a central regulator of cancer progression
.
Trends Cell Biol
2015
;
25
:
675
86
.
78.
Bakir
B
,
Chiarella
AM
,
Pitarresi
JR
,
Rustgi
AK
.
EMT, MET, plasticity, and tumor metastasis
.
Trends Cell Biol
2020
;
30
:
764
76
.
79.
Lambert
AW
,
Weinberg
RA
.
Linking EMT programs to normal and neoplastic epithelial stem cells
.
Nat Rev Cancer
2021
;
21
:
325
38
.
80.
Micalizzi
DS
,
Ebright
RY
,
Haber
DA
,
Maheswaran
S
.
Translational regulation of cancer metastasis
.
Cancer Res
2021
;
81
:
517
24
.
81.
Dass
RA
,
Sarshad
AA
,
Carson
BB
,
Feenstra
JM
,
Kaur
A
,
Obrdlik
A
, et al
.
Wnt5a signals through DVL1 to repress ribosomal DNA transcription by RNA polymerase I
.
PLoS Genet
2016
;
12
:
e1006217
.
82.
Prakash
V
,
Carson
BB
,
Feenstra
JM
,
Dass
RA
,
Sekyrova
P
,
Hoshino
A
, et al
.
Ribosome biogenesis during cell-cycle arrest fuels EMT in development and disease
.
Nat Commun
2019
;
10
:
2110
.
83.
Kudo
M
,
Anam
MB
,
Istiaq
A
,
Ahmad
SAI
,
Ito
N
,
Ohta
K
.
Ribosome incorporation induces EMT-like phenomenon with cell-cycle arrest in human breast cancer cell
.
Cells Tissues Organs
2021
;
211
:
212
21
.
84.
Chu
W
,
Zhang
X
,
Qi
L
,
Fu
Y
,
Wang
P
,
Zhao
W
, et al
.
The EZH2-PHACTR2-AS1-ribosome axis induces genomic instability and promotes growth and metastasis in breast cancer
.
Cancer Res
2020
;
80
:
2737
50
.
85.
Ebright
RY
,
Lee
S
,
Wittner
BS
,
Niederhoffer
KL
,
Nicholson
BT
,
Bardia
A
, et al
.
Deregulation of ribosomal protein expression and translation promotes breast cancer metastasis
.
Science
2020
;
367
:
1468
73
.
86.
Zhao
W
,
Li
X
,
Nian
W
,
Wang
J
,
Wang
X
,
Sun
L
, et al
.
Ribosome proteins represented by RPL27A mark the development and metastasis of triple-negative breast cancer in mouse and human
.
Front Cell Dev Biol
2021
;
9
:
716730
.
87.
Dermit
M
,
Dodel
M
,
Lee
FCY
,
Azman
MS
,
Schwenzer
H
,
Jones
JL
, et al
.
Subcellular mRNA localization regulates ribosome biogenesis in migrating cells
.
Dev Cell
2020
;
55
:
298
313
.
88.
Russo
A
,
Saide
A
,
Cagliani
R
,
Cantile
M
,
Botti
G
,
Russo
G
.
rpL3 promotes the apoptosis of p53 mutated lung cancer cells by downregulating CBS and NFkappaB upon 5-FU treatment
.
Sci Rep
2016
;
6
:
38369
.
89.
Wu
Q
,
Gou
Y
,
Wang
Q
,
Jin
H
,
Cui
L
,
Zhang
Y
, et al
.
Downregulation of RPL6 by siRNA inhibits proliferation and cell-cycle progression of human gastric cancer cell lines
.
PLoS One
2011
;
6
:
e26401
.
90.
Du
J
,
Shi
Y
,
Pan
Y
,
Jin
X
,
Liu
C
,
Liu
N
, et al
.
Regulation of multidrug resistance by ribosomal protein l6 in gastric cancer cells
.
Cancer Biol Ther
2005
;
4
:
242
7
.
91.
Kobayashi
T
,
Sasaki
Y
,
Oshima
Y
,
Yamamoto
H
,
Mita
H
,
Suzuki
H
, et al
.
Activation of the ribosomal protein L13 gene in human gastrointestinal cancer
.
Int J Mol Med
2006
;
18
:
161
70
.
92.
Shi
Y
,
Zhai
H
,
Wang
X
,
Han
Z
,
Liu
C
,
Lan
M
, et al
.
Ribosomal proteins S13 and L23 promote multidrug resistance in gastric cancer cells by suppressing drug-induced apoptosis
.
Exp Cell Res
2004
;
296
:
337
46
.
93.
Wei
F
,
Ding
L
,
Wei
Z
,
Zhang
Y
,
Li
Y
,
Qinghua
L
, et al
.
Ribosomal protein L34 promotes the proliferation, invasion, and metastasis of pancreatic cancer cells
.
Oncotarget
2016
;
7
:
85259
72
.
94.
Gambardella
V
,
Gimeno-Valiente
F
,
Tarazona
N
,
Martinez-Ciarpaglini
C
,
Roda
D
,
Fleitas
T
, et al
.
NRF2 through RPS6 activation is related to anti-HER2 drug resistance in HER2-amplified gastric cancer
.
Clin Cancer Res
2019
;
25
:
1639
49
.
95.
Kim
W
,
Youn
H
,
Lee
S
,
Kim
E
,
Kim
D
,
Sub
Lee J
, et al
.
RNF138-mediated ubiquitination of rpS3 is required for resistance of glioblastoma cells to radiation-induced apoptosis
.
Exp Mol Med
2018
;
50
:
e434
.
96.
Yang
HJ
,
Youn
H
,
Seong
KM
,
Jin
YW
,
Kim
J
,
Youn
B
.
Phosphorylation of ribosomal protein S3 and antiapoptotic TRAF2 protein mediates radioresistance in non–small cell lung cancer cells
.
J Biol Chem
2013
;
288
:
2965
75
.
97.
Awah
CU
,
Chen
L
,
Bansal
M
,
Mahajan
A
,
Winter
J
,
Lad
M
, et al
.
Ribosomal protein S11 influences glioma response to TOP2 poisons
.
Oncogene
2020
;
39
:
5068
81
.
98.
Guo
X
,
Shi
Y
,
Gou
Y
,
Li
J
,
Han
S
,
Zhang
Y
, et al
.
Human ribosomal protein S13 promotes gastric cancer growth through downregulating p27(Kip1)
.
J Cell Mol Med
2011
;
15
:
296
306
.
99.
Wang
H
,
Xie
B
,
Kong
Y
,
Tao
Y
,
Yang
G
,
Gao
M
, et al
.
Overexpression of RPS27a contributes to enhanced chemoresistance of CML cells to imatinib by the transactivated STAT3
.
Oncotarget
2016
;
7
:
18638
50
.
100.
Zhao
Y
,
Tan
M
,
Liu
X
,
Xiong
X
,
Sun
Y
.
Inactivation of ribosomal protein S27-like confers radiosensitivity via the Mdm2-p53 and Mdm2-MRN-ATM axes
.
Cell Death Dis
2018
;
9
:
145
.
101.
Williams
PD
,
Owens
CR
,
Dziegielewski
J
,
Moskaluk
CA
,
Read
PW
,
Larner
JM
, et al
.
Cyclophilin B expression is associated with in vitro radioresistance and clinical outcome after radiotherapy
.
Neoplasia
2011
;
13
:
1122
31
.
102.
Sapio
RT
,
Nezdyur
AN
,
Krevetski
M
,
Anikin
L
,
Manna
VJ
,
Minkovsky
N
, et al
.
Inhibition of posttranscriptional steps in ribosome biogenesis confers cytoprotection against chemotherapeutic agents in a p53-dependent manner
.
Sci Rep
2017
;
7
:
9041
.
103.
Ko
CY
,
Lin
CH
,
Chuang
JY
,
Chang
WC
,
Hsu
TI
.
MDM2 Degrades deacetylated nucleolin through ubiquitination to promote glioma stem-like cell enrichment for chemotherapeutic resistance
.
Mol Neurobiol
2018
;
55
:
3211
23
.
104.
Janin
M
,
Ortiz-Barahona
V
,
de Moura
MC
,
Martinez-Cardus
A
,
Llinas-Arias
P
,
Soler
M
, et al
.
Epigenetic loss of RNA-methyltransferase NSUN5 in glioma targets ribosomes to drive a stress adaptive translational program
.
Acta Neuropathol
2019
;
138
:
1053
74
.
105.
Meng
W
,
Wang
PS
,
Liu
J
,
Xue
S
,
Wang
GM
,
Meng
XY
, et al
.
Adenovirus-mediated siRNA targeting NOB1 inhibits tumor growth and enhances radiosensitivity of human papillary thyroid carcinoma in vitro and in vivo
.
Oncol Rep
2014
;
32
:
2411
20
.
106.
Burger
K
,
Muhl
B
,
Harasim
T
,
Rohrmoser
M
,
Malamoussi
A
,
Orban
M
, et al
.
Chemotherapeutic drugs inhibit ribosome biogenesis at various levels
.
J Biol Chem
2010
;
285
:
12416
25
.
107.
Bruno
PM
,
Liu
Y
,
Park
GY
,
Murai
J
,
Koch
CE
,
Eisen
TJ
, et al
.
A subset of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress
.
Nat Med
2017
;
23
:
461
71
.
108.
Gilder
AS
,
Do
PM
,
Carrero
ZI
,
Cosman
AM
,
Broome
HJ
,
Velma
V
, et al
.
Coilin participates in the suppression of RNA polymerase I in response to cisplatin-induced DNA damage
.
Mol Biol Cell
2011
;
22
:
1070
9
.
109.
Likovsky
Z
,
Peterka
M
,
Peterkova
R
.
Drug-induced changes of rRNA biosynthesis–a marker of toxic damage to embryonal cell population
.
Funct Dev Morphol
1993
;
3
:
3
9
.
110.
Kacerovska
H
,
Likovsky
Z
,
Smetana
K
.
Nucleolar silver stained granules in rat Yoshida sarcoma cells after RNA synthesis inhibition
.
Neoplasma
1981
;
28
:
513
6
.
111.
Deisenroth
C
,
Zhang
Y
.
Ribosome biogenesis surveillance: probing the ribosomal protein-Mdm2-p53 pathway
.
Oncogene
2010
;
29
:
4253
60
.
112.
Haddach
M
,
Schwaebe
MK
,
Michaux
J
,
Nagasawa
J
,
O'Brien
SE
,
Whitten
JP
, et al
.
Discovery of CX-5461, the first direct and selective inhibitor of RNA polymerase I, for cancer therapeutics
.
ACS Med Chem Lett
2012
;
3
:
602
6
.
113.
Drygin
D
,
Lin
A
,
Bliesath
J
,
Ho
CB
,
O'Brien
SE
,
Proffitt
C
, et al
.
Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth
.
Cancer Res
2011
;
71
:
1418
30
.
114.
Quin
J
,
Chan
KT
,
Devlin
JR
,
Cameron
DP
,
Diesch
J
,
Cullinane
C
, et al
.
Inhibition of RNA polymerase I transcription initiation by CX-5461 activates noncanonical ATM/ATR signaling
.
Oncotarget
2016
;
7
:
49800
18
.
115.
Negi
SS
,
Brown
P
.
rRNA synthesis inhibitor, CX-5461, activates ATM/ATR pathway in acute lymphoblastic leukemia, arrests cells in G2 phase and induces apoptosis
.
Oncotarget
2015
;
6
:
18094
104
.
116.
Hein
N
,
Cameron
DP
,
Hannan
KM
,
Nguyen
NN
,
Fong
CY
,
Sornkom
J
, et al
.
Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population
.
Blood
2017
;
129
:
2882
95
.
117.
Maclachlan
KH
,
Cuddihy
A
,
Hein
N
,
Cullinane
C
,
Harrison
SJ
,
Hannan
R
, et al
.
Novel combination therapies with the RNA polymerase I inhibitor CX-5461 significantly improve efficacy in multiple myeloma
.
Blood
2017
;
130
:
1805
.
118.
Lee
HC
,
Wang
H
,
Baladandayuthapani
V
,
Lin
H
,
He
J
,
Jones
RJ
, et al
.
RNA polymerase I inhibition with CX-5461 as a novel therapeutic strategy to target myc in multiple myeloma
.
Brit J Haematol
2017
;
177
:
80
94
.
119.
Cornelison
R
,
Dobbin
ZC
,
Katre
AA
,
Jeong
DH
,
Zhang
Y
,
Chen
D
, et al
.
Targeting RNA-polymerase I in both chemosensitive and chemoresistant populations in epithelial ovarian cancer
.
Clin Cancer Res
2017
;
23
:
6529
40
.
120.
Sanij
E
,
Hannan
KM
,
Xuan
J
,
Yan
S
,
Ahern
JE
,
Trigos
AS
, et al
.
CX-5461 activates the DNA damage response and demonstrates therapeutic efficacy in high-grade serous ovarian cancer
.
Nat Commun
2020
;
11
:
2641
.
121.
Lawrence
MG
,
Porter
LH
,
Choo
N
,
Pook
D
,
Grummet
JP
,
Pezaro
CJ
, et al
.
CX-5461 sensitizes DNA damage repair–proficient castrate-resistant prostate cancer to PARP inhibition
.
Mol Cancer Ther
2021
;
20
:
2140
50
.
122.
Peltonen
K
,
Colis
L
,
Liu
H
,
Jaamaa
S
,
Moore
HM
,
Enback
J
, et al
.
Identification of novel p53 pathway activating small-molecule compounds reveals unexpected similarities with known therapeutic agents
.
PLoS One
2010
;
5
:
e12996
.
123.
Peltonen
K
,
Colis
L
,
Liu
H
,
Trivedi
R
,
Moubarek
MS
,
Moore
HM
, et al
.
A targeting modality for destruction of RNA polymerase I that possesses anticancer activity
.
Cancer Cell
2014
;
25
:
77
90
.
124.
Low
JY
,
Sirajuddin
P
,
Moubarek
M
,
Agarwal
S
,
Rege
A
,
Guner
G
, et al
.
Effective targeting of RNA polymerase I in treatment-resistant prostate cancer
.
Prostate
2019
;
79
:
1837
51
.
125.
Guner
G
,
Sirajuddin
P
,
Zheng
Q
,
Bai
B
,
Brodie
A
,
Liu
H
, et al
.
Novel assay to detect RNA polymerase I activity in vivo
.
Mol Cancer Res
2017
;
15
:
577
84
.
126.
Fu
X
,
Xu
L
,
Qi
L
,
Tian
H
,
Yi
D
,
Yu
Y
, et al
.
BMH-21 inhibits viability and induces apoptosis by p53-dependent nucleolar stress responses in SKOV3 ovarian cancer cells
.
Oncol Rep
2017
;
38
:
859
65
.
127.
Kammerud
SC
,
Metge
BJ
,
Elhamamsy
AR
,
Weeks
SE
,
Alsheikh
HA
,
Mattheyses
AL
, et al
.
Novel role of the dietary flavonoid fisetin in suppressing rRNA biogenesis
.
Lab Invest
2021
;
101
:
1439
48
.
128.
Dauban
L
,
Cerezo
E
,
Henras
A
,
Gadal
O
.
Meeting report from the first European OddPols meeting: Toulouse 2018
.
Gene
2019
;
702
:
215
9
.
129.
Frankowski
K
,
Patnaik
S
,
Schoenen
F
,
Huang
S
,
Norton
J
,
Wang
C
, et al
.
Discovery and development of small molecules that reduce PNC prevalence
. In:
Probe reports from the NIH Molecular Libraries Program [Internet]
.
Bethesda, MD
:
National Center for Biotechnology Information
;
2010
.
130.
Slusarczyk
A
,
Kamath
R
,
Wang
C
,
Anchel
D
,
Pollock
C
,
Lewandowska
MA
, et al
.
Structure and function of the perinucleolar compartment in cancer cells
.
Cold Spring Harb Symp Quant Biol
2010
;
75
:
599
605
.
131.
Kamath
RV
,
Thor
AD
,
Wang
C
,
Edgerton
SM
,
Slusarczyk
A
,
Leary
DJ
, et al
.
Perinucleolar compartment prevalence has an independent prognostic value for breast cancer
.
Cancer Res
2005
;
65
:
246
53
.
132.
Norton
JT
,
Pollock
CB
,
Wang
C
,
Schink
JC
,
Kim
JJ
,
Huang
S
.
Perinucleolar compartment prevalence is a phenotypic pancancer marker of malignancy
.
Cancer
2008
;
113
:
861
9
.
133.
Norton
JT
,
Titus
SA
,
Dexter
D
,
Austin
CP
,
Zheng
W
,
Huang
S
.
Automated high-content screening for compounds that disassemble the perinucleolar compartment
.
J Biomol Screen
2009
;
14
:
1045
53
.
134.
Frankowski
KJ
,
Wang
C
,
Patnaik
S
,
Schoenen
FJ
,
Southall
N
,
Li
D
, et al
.
Metarrestin, a perinucleolar compartment inhibitor, effectively suppresses metastasis
.
Sci Transl Med
2018
;
10
:
eaap8307
.
135.
Grzmil
M
,
Hemmings
BA
.
Translation regulation as a therapeutic target in cancer
.
Cancer Res
2012
;
72
:
3891
900
.
136.
Silvera
D
,
Formenti
SC
,
Schneider
RJ
.
Translational control in cancer
.
Nat Rev Cancer
2010
;
10
:
254
66
.
137.
Caudron-Herger
M
,
Pankert
T
,
Seiler
J
,
Nemeth
A
,
Voit
R
,
Grummt
I
, et al
.
Alu element-containing RNAs maintain nucleolar structure and function
.
EMBO J
2015
;
34
:
2758
74
.
138.
Abraham
KJ
,
Khosraviani
N
,
Chan
JNY
,
Gorthi
A
,
Samman
A
,
Zhao
DY
, et al
.
Nucleolar RNA polymerase II drives ribosome biogenesis
.
Nature
2020
;
585
:
298
302
.
139.
Hao
Q
,
Prasanth
KV
.
Regulatory roles of nucleolus organizer region-derived long non-coding RNAs
.
Mamm Genome
2021
.
140.
Shiao
YH
,
Lupascu
ST
,
Gu
YD
,
Kasprzak
W
,
Hwang
CJ
,
Fields
JR
, et al
.
An intergenic non-coding rRNA correlated with expression of the rRNA and frequency of an rRNA single nucleotide polymorphism in lung cancer cells
.
PLoS One
2009
;
4
:
e7505
.
141.
Yan
Q
,
Zhu
C
,
Guang
S
,
Feng
X
.
The functions of non-coding RNAs in rRNA regulation
.
Front Genet
2019
;
10
:
290
.