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

Karita Peltonen, Laureen Colis, Hester Liu, Rishi Trivedi, Michael S. Moubarek, Henna M. Moore, Baoyan Bai, Michelle A. Rudek, Charles J. Bieberich, Marikki Laiho

Research output: Contribution to journalArticlepeer-review

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 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.

Original languageEnglish (US)
Pages (from-to)77-90
Number of pages14
JournalCancer cell
Volume25
Issue number1
DOIs
StatePublished - Jan 13 2014

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Fingerprint Dive into the research topics of 'A targeting modality for destruction of RNA polymerase I that possesses anticancer activity'. Together they form a unique fingerprint.

Cite this