title: A targeting modality for destruction of RNA polymerase I that possesses anticancer activity.
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.
authors.affiliation: Molecular Cancer Biology Program and Centre for Drug Research, University of Helsinki, Helsinki 00014, Finland.
authors.forename: Karita
authors.initials: K
authors.lastname: Peltonen
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Laureen
authors.initials: L
authors.lastname: Colis
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Hester
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Rishi
authors.initials: R
authors.lastname: Trivedi
authors.affiliation: Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Moubarek
authors.affiliation: Molecular Cancer Biology Program and Centre for Drug Research, University of Helsinki, Helsinki 00014, Finland.
authors.forename: Henna M
authors.initials: HM
authors.lastname: Moore
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Baoyan
authors.initials: B
authors.lastname: Bai
authors.affiliation: Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.affiliation: Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250, USA.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Bieberich
authors.affiliation: 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.
authors.forename: Marikki
authors.initials: M
authors.lastname: Laiho
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D047369:Chromatin Immunoprecipitation; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D012318:RNA Polymerase I / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D012318:RNA Polymerase I; D046988:Proteasome Endopeptidase Complex