期刊
CANCER CELL
卷 25, 期 1, 页码 77-90出版社
CELL PRESS
DOI: 10.1016/j.ccr.2013.12.009
关键词
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资金
- Academy of Finland [251307]
- Finnish Cancer Organizations
- Patrick C. Walsh Prostate Cancer Research Fund
- NIH [P50 CA058236, P30 CA006973]
- Johns Hopkins University
- Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins [NIH P30 CA006973, NIH UL1 RR025005, NIH 1S10RR026824-01]
- Biomedicum Helsinki Foundation
- Cancer Society Finland
- Finnish Cultural Foundation
- Academy of Finland (AKA) [251307, 251307] Funding Source: Academy of Finland (AKA)
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 in vivo. BMH-21 binds GC-rich sequences, which are present at a high frequency in ribosomal DNA genes, and potently and rapidly represses RNA polynnerase I (Poll) 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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