Inhibition of RNA Polymerase I as a Therapeutic Strategy to Promote Cancer-Specific Activation of p53
Bywater, Megan J.; Hannan, Ross; Poortinga, Gretchen; Sanij, Elaine; Peck, Abigail; Cullinane, C; Wall, Meaghan; Cluse, Leonie A.; Drygin, Denis; Anderes, Kenna; Huser, Nanni; Proffitt, Chris; Bliesath, Joshua; Haddach, Mustapha; Schwaebe, Michael K; Ryckman, David M; Rice, William G; Schmitt, Clemens; Lowe, Scott W.; Johnstone, Ricky; Pearson, Richard B; McArthur, Grant; Hein, Nadine
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....[Show more]
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