TY - JOUR
T1 - A targeting modality for destruction of RNA polymerase I that possesses anticancer activity
AU - Peltonen, Karita
AU - Colis, Laureen
AU - Liu, Hester
AU - Trivedi, Rishi
AU - Moubarek, Michael S.
AU - Moore, Henna M.
AU - Bai, Baoyan
AU - Rudek, Michelle A.
AU - Bieberich, Charles J.
AU - Laiho, Marikki
N1 - Funding Information:
We thank Dr. Claus Storgaard Sørensen and Carina I. Holmberg for helpful discussions, Kaisa Penttilä for technical assistance, Dr. Brian McStay and Dr. Ingrid Grummt for reagents, and NCI Developmental Therapeutics Program for performing the NCI60 cell line screen. This work has been supported by the Academy of Finland (251307), Finnish Cancer Organizations, the Patrick C. Walsh Prostate Cancer Research Fund, NIH P50 CA058236, NIH P30 CA006973, Johns Hopkins University start-up funds, and the Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (NIH P30 CA006973, NIH UL1 RR025005, and the Shared Instrument Grant [NIH 1S10RR026824-01]). K.P. was supported by the Biomedicum Helsinki Foundation, Cancer Society Finland, and the Finnish Cultural Foundation.
PY - 2014/1/13
Y1 - 2014/1/13
N2 - We define the activity and mechanisms of action of a small molecule lead compound for cancer targeting. We show that the compound, BMH-21, has wide and potent antitumorigenic activity across NCI60 cancer cell lines and represses tumor growth invivo. BMH-21 binds GC-rich sequences, which are present at a high frequency in ribosomal DNA genes, and potently and rapidly represses RNA polymerase I (Pol I) transcription. Strikingly, we find that BMH-21 causes proteasome-dependent destruction of RPA194, the large catalytic subunit protein of Pol I holocomplex, and this correlates with cancer cell killing. Our results show that Pol I activity is under proteasome-mediated control, which reveals an unexpected therapeutic opportunity.
AB - We define the activity and mechanisms of action of a small molecule lead compound for cancer targeting. We show that the compound, BMH-21, has wide and potent antitumorigenic activity across NCI60 cancer cell lines and represses tumor growth invivo. BMH-21 binds GC-rich sequences, which are present at a high frequency in ribosomal DNA genes, and potently and rapidly represses RNA polymerase I (Pol I) transcription. Strikingly, we find that BMH-21 causes proteasome-dependent destruction of RPA194, the large catalytic subunit protein of Pol I holocomplex, and this correlates with cancer cell killing. Our results show that Pol I activity is under proteasome-mediated control, which reveals an unexpected therapeutic opportunity.
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U2 - 10.1016/j.ccr.2013.12.009
DO - 10.1016/j.ccr.2013.12.009
M3 - Article
C2 - 24434211
AN - SCOPUS:84892409069
SN - 1535-6108
VL - 25
SP - 77
EP - 90
JO - Cancer cell
JF - Cancer cell
IS - 1
ER -