Inhibition of RNA Polymerase I as a Therapeutic Strategy to Promote Cancer-Specific Activation of p53

Bywater, Megan J.; Poortinga, Gretchen; Sanij, Elaine; Hein, Nadine; Peck, Abigail; Cullinane, Carleen; Wall, Meaghan; Cluse, Leonie A.; Drygin, Denis; Anderes, Kenna; Huser, Nanni; Proffitt, Chris; Bliesath, Josh; Haddach, Mustapha; Schwaebe, Michael K.; Ryckman, David M.; Rice, William G.; Schmitt, Clemens A.; Lowe, Scott W.; Johnstone, Ricky W.; Pearson, Richard B.; McArthur, Grant A.; Hannan, Ross D.

doi:10.1016/j.ccr.2012.05.019

Cited by 479 publications

(674 citation statements)

References 38 publications

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“…The data suggest that targeting the nucleolar proteome may elicit the required signaling events to cell cycle regulators without affecting rRNA production and ribosome biosynthesis. This may be important as targetting Pol I activity is emerging as an attractive anti cancer approach 55,56,57 .…”

Section: Discussionmentioning

confidence: 99%

The NEDD8 inhibitor MLN4924 increases the size of the nucleolus and activates p53 through the ribosomal-Mdm2 pathway

et al. 2015

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The NEDD8 inhibitor MLN4924 increases the size of the nucleolus and activates p53 through the ribosomal-Mdm2 pathway Bailly, A.; Perrin, A.; Bou Malhab, L. J.; Pion, E.; Larance, M.; Nagala, M.; Smith, P.; O'Donohue, M.-F.; Gleizes, P.-E.; Zomerdijk, Josephus; Lamond, Angus; Xirodimas, D. P. Published in: Oncogene DOI:10.1038/onc.2015.104 Publication date: 2016 Document VersionPeer reviewed version Link to publication in Discovery Research Portal Citation for published version (APA):Bailly, A., Perrin, A., Bou Malhab, L. J., Pion, E., Larance, M., Nagala, M., ... Xirodimas, D. P. (2016). The NEDD8 inhibitor MLN4924 increases the size of the nucleolus and activates p53 through the ribosomal-Mdm2 pathway. Oncogene, 35(4), 415-426. DOI: 10.1038415-426. DOI: 10. /onc.2015 General rights Copyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain.• You may freely distribute the URL identifying the publication in the public portal. Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

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Section: Discussionmentioning

confidence: 99%

The NEDD8 inhibitor MLN4924 increases the size of the nucleolus and activates p53 through the ribosomal-Mdm2 pathway

et al. 2015

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“…2, 9-11]. In particular, the robust upregulation of genes encoding all members of the RNA polymerase I (Pol I) complex, which is responsible for transcription of the 47S pre-rRNA encoding genes (rDNA), is a key component of MYC's gene expression signature (9,10,12,13). Importantly, we recently demonstrated that rDNA transcription, a key ratelimiting step for ribosome biogenesis, is specifically targeted by the novel small-molecule inhibitor CX-5461, which is currently in phase I trial (14).…”

Section: Research Briefmentioning

confidence: 99%

Combination Therapy Targeting Ribosome Biogenesis and mRNA Translation Synergistically Extends Survival in MYC-Driven Lymphoma

et al. 2016

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Ribosome biogenesis and protein synthesis are dysregulated in many cancers, with those driven by the proto-oncogene c-MYC characterized by elevated Pol I-mediated ribosomal rDNA transcription and mTORC1/eIF4E-driven mRNA translation. Here, we demonstrate that coordinated targeting of rDNA transcription and PI3K-AKT-mTORC1-dependent ribosome biogenesis and protein synthesis provides a remarkable improvement in survival in MYCdriven B lymphoma. Combining an inhibitor of rDNA transcription (CX-5461) with the mTORC1 inhibitor everolimus more than doubled survival of Eμ-Myc lymphoma-bearing mice. The ability of each agent to trigger tumor cell death via independent pathways was central to their synergistic efficacy. CX-5461 induced nucleolar stress and p53 pathway activation, whereas everolimus induced expression of the proapoptotic protein BMF that was independent of p53 and reduced expression of RPL11 and RPL5. Thus, targeting the network controlling the synthesis and function of ribosomes at multiple points provides a potential new strategy to treat MYC-driven malignancies. SIGNIFICANCE:Treatment options for the high proportion of cancers driven by MYC are limited. We demonstrate that combining pharmacologic targeting of ribosome biogenesis and mTORC1-dependent translation provides a remarkable therapeutic benefit to Eμ-Myc lymphoma-bearing mice. These results establish a rationale for targeting ribosome biogenesis and function to treat MYC-driven cancer. Cancer Discov; 6(1);[59][60][61][62][63][64][65][66][67][68][69][70]

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“…The RNA Pol I inhibitor CX5461 has shown therapeutic potential in mouse leukemia model. 17 It will be important to investigate the role of RNA Pol I inhibition in solid tumors that have low apoptotic potential and rely on senescence as a treatment response mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…Recently the RNA Pol Ispecific inhibitor CX5461 has shown promise as an anti-tumor agent in animal models, in part by activating p53 through the nucleolar stress signaling mechanism that inhibits MDM2 function. 16,17 Nearly 50% of rDNA repeats are present as heterochromatin in growing cells, which is important for maintaining genetic stability. 18 The NoRC (nucleolar remodeling complex) is important for switching rDNA between silent and active state.…”

Section: Introductionmentioning

confidence: 99%

Nucleolar repression facilitates initiation and maintenance of senescence

Yang

Song

Soliman³

et al. 2015

Cell Cycle

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Tumor cells with defective apoptosis pathways often respond to chemotherapy by entering irreversible cell cycle arrest with features of senescence. However, rare cells can bypass entry to senescence, or re-enter cell cycle from a senescent state. Deficiency in senescence induction and maintenance may contribute to treatment resistance and early relapse after therapy. Senescence involves epigenetic silencing of cell cycle genes and reduced rRNA transcription. We found that senescence-inducing treatments such as DNA damage and RNA polymerase I inhibition stimulate the binding between the nucleolar protein NML (nucleomethylin) and SirT1. The NML complex promotes rDNA heterochromatin formation and represses rRNA transcription. Depletion of NML reduced the levels of H3K9Me3 and H3K27Me3 heterochromatin markers on rDNA and E2F1 target promoters in senescent cells, increased rRNA transcription, and increased the frequency of cell cycle re-entry. Depletion of the nucleolar transcription repressor factor TIP5 also promoted escape from senescence. Furthermore, tumor tissue staining showed that breast tumors without detectable nucleolar NML expression had poor survival. The results suggest that efficient regulation of nucleolar rDNA transcription facilitates the maintenance of irreversible cell cycle arrest in senescent cells. Deficiency in nucleolar transcription repression may accelerate tumor relapse after chemotherapy.

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Inhibition of RNA Polymerase I as a Therapeutic Strategy to Promote Cancer-Specific Activation of p53

Cited by 479 publications

References 38 publications

The NEDD8 inhibitor MLN4924 increases the size of the nucleolus and activates p53 through the ribosomal-Mdm2 pathway

The NEDD8 inhibitor MLN4924 increases the size of the nucleolus and activates p53 through the ribosomal-Mdm2 pathway

Combination Therapy Targeting Ribosome Biogenesis and mRNA Translation Synergistically Extends Survival in MYC-Driven Lymphoma

Nucleolar repression facilitates initiation and maintenance of senescence

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