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Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53

Item Type:Article
Title:Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53
Creators Name:Bywater, M.J. and Poortinga, G. and Sanij, E. and Hein, N. and Peck, A. and Cullinane, C. and Wall, M. and Cluse, L. and Drygin, D. and Anderes, K. and Huser, N. and Proffitt, C. and Bliesath, J. and Haddach, M. and Schwaebe, M.K. and Ryckman, D.M. and Rice, W.G. and Schmitt, C. and Lowe, S.W. and Johnstone, R.W. and Pearson, R.B. and McArthur, G.A. and Hannan, R.D.
Abstract:Increased transcription of ribosomal RNA genes (rDNA) by RNA Polymerase I is a common feature of human cancer, but whether it is required for the malignant phenotype remains unclear. We show that rDNA transcription can be therapeutically targeted with the small molecule CX-5461 to selectively kill B-lymphoma cells in vivo while maintaining a viable wild-type B cell population. The therapeutic effect is a consequence of nucleolar disruption and activation of p53-dependent apoptotic signaling. Human leukemia and lymphoma cell lines also show high sensitivity to inhibition of rDNA transcription that is dependent on p53 mutational status. These results identify selective inhibition of rDNA transcription as a therapeutic strategy for the cancer specific activation of p53 and treatment of hematologic malignancies.
Keywords:Apoptosis, Benzothiazoles, Naphthyridines, Neoplasms, Genetic Transcription, Ribosomal DNA, RNA Polymerase, Ribosomal RNA, Transgenic Mice, Tumor Suppressor Protein p53, Animals, Mice
Source:Cancer Cell
Publisher:Cell Press / Elsevier
Page Range:51-65
Date:10 July 2012
Official Publication:https://doi.org/10.1016/j.ccr.2012.05.019
PubMed:View item in PubMed

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