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

  • Cancer Cell. 2014 Jan 13;25(1):77-90. doi: 10.1016/j.ccr.2013.12.009.
Karita Peltonen  1 ,  Laureen Colis  2 ,  Hester Liu  2 ,  Rishi Trivedi  2 ,  Michael S Moubarek  3 ,  Henna M Moore  1 ,  Baoyan Bai  2 ,  Michelle A Rudek  4 ,  Charles J Bieberich  3 ,  Marikki Laiho  5
Affiliations
  • 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: [email protected].
PMID: 24434211 DOI: 10.1016/j.ccr.2013.12.009
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.

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