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

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

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291 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)51 - 65
Number of pages15
JournalCancer Cell
Volume22
Issue number1
DOIs
Publication statusPublished - 2012

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