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Cancer Cell. 2014 Jan 13;25(1):77-90. doi: 10.1016/j.ccr.2013.12.009.

A targeting modality for destruction of RNA polymerase I that possesses anticancer activity.

Author information

1
Molecular Cancer Biology Program and Centre for Drug Research, University of Helsinki, Helsinki 00014, Finland.
2
Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
3
Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250, USA.
4
Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
5
Molecular Cancer Biology Program and Centre for Drug Research, University of Helsinki, Helsinki 00014, Finland; Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Electronic address: mlaiho1@jhmi.edu.

Abstract

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 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.

PMID:
24434211
PMCID:
PMC3930145
DOI:
10.1016/j.ccr.2013.12.009
[Indexed for MEDLINE]
Free PMC Article
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