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Cancer Cell. 2012 Jul 10;22(1):51-65. doi: 10.1016/j.ccr.2012.05.019.

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

Author information

1
Division of Cancer Research, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria 3002, Australia.

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.

PMID:
22789538
PMCID:
PMC3749732
DOI:
10.1016/j.ccr.2012.05.019
[Indexed for MEDLINE]
Free PMC Article
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