Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53.
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.
Division of Cancer Research, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria 3002, Australia.
Megan J
MJ
Bywater
Gretchen
G
Poortinga
Elaine
E
Sanij
Nadine
N
Hein
Abigail
A
Peck
Carleen
C
Cullinane
Meaghan
M
Wall
Leonie
L
Cluse
Denis
D
Drygin
Kenna
K
Anderes
Nanni
N
Huser
Chris
C
Proffitt
Joshua
J
Bliesath
Mustapha
M
Haddach
Michael K
MK
Schwaebe
David M
DM
Ryckman
William G
WG
Rice
Clemens
C
Schmitt
Scott W
SW
Lowe
Ricky W
RW
Johnstone
Richard B
RB
Pearson
Grant A
GA
McArthur
Ross D
RD
Hannan
D000818:Animals; D017209:Apoptosis; D052160:Benzothiazoles / Q000494:pharmacology; D004275:DNA, Ribosomal / Q000235:genetics; D005260:Female; D051379:Mice; D008822:Mice, Transgenic; D009287:Naphthyridines / Q000494:pharmacology; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012318:RNA Polymerase I / Q000037:antagonists & inhibitors*; D012335:RNA, Ribosomal / Q000235:genetics; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D052160:Benzothiazoles; C557717:CX 5461; D004275:DNA, Ribosomal; D009287:Naphthyridines; D012335:RNA, Ribosomal; D016159:Tumor Suppressor Protein p53; D012318:RNA Polymerase I