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

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.

SUBMITTER: Bywater MJ

PROVIDER: S-EPMC3749732 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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

Bywater Megan J MJ Poortinga Gretchen G Sanij Elaine E Hein Nadine N Peck Abigail A Cullinane Carleen C Wall Meaghan M Cluse Leonie L Drygin Denis D Anderes Kenna K Huser Nanni N Proffitt Chris C Bliesath Joshua J Haddach Mustapha M Schwaebe Michael K MK Ryckman David M DM Rice William G WG Schmitt Clemens C Lowe Scott W SW Johnstone Ricky W RW Pearson Richard B RB McArthur Grant A GA Hannan Ross D RD

Cancer cell 20120701 1

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. Hum ...[more]

PMID: 22789538

Dataset Information

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

Publications

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

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