title: Old drug, new target: ellipticines selectively inhibit RNA polymerase I transcription.
abstract: Transcription by RNA polymerase I (Pol-I) is the main driving force behind ribosome biogenesis, a fundamental cellular process that requires the coordinated transcription of all three nuclear polymerases. Increased Pol-I transcription and the concurrent increase in ribosome biogenesis has been linked to the high rates of proliferation in cancers. The ellipticine family contains a number of potent anticancer therapeutic agents, some having progressed to stage I and II clinical trials; however, the mechanism by which many of the compounds work remains unclear. It has long been thought that inhibition of Top2 is the main reason behind the drugs antiproliferative effects. Here we report that a number of the ellipticines, including 9-hydroxyellipticine, are potent and specific inhibitors of Pol-I transcription, with IC(50) in vitro and in cells in the nanomolar range. Essentially, the drugs did not affect Pol-II and Pol-III transcription, demonstrating a high selectivity. We have shown that Pol-I inhibition occurs by a p53-, ATM/ATR-, and Top2-independent mechanism. We discovered that the drug influences the assembly and stability of preinitiation complexes by targeting the interaction between promoter recognition factor SL1 and the rRNA promoter. Our findings will have an impact on the design and development of novel therapeutic agents specifically targeting ribosome biogenesis.
authors.affiliation: School of Biological Sciences, The Queen’s University Belfast, Belfast BT9 7BL, United Kingdom.
authors.forename: William J
authors.initials: WJ
authors.lastname: Andrews
authors.forename: Tatiana
authors.initials: T
authors.lastname: Panova
authors.forename: Christophe
authors.initials: C
authors.lastname: Normand
authors.forename: Olivier
authors.initials: O
authors.lastname: Gadal
authors.forename: Irina G
authors.initials: IG
authors.lastname: Tikhonova
authors.forename: Konstantin I
authors.initials: KI
authors.lastname: Panov
mesh_terms: D001973:Bromodeoxyuridine / Q000494:pharmacology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D004611:Ellipticines / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008954:Models, Biological; D008956:Models, Chemical; D008958:Models, Molecular; D035463:Pol1 Transcription Initiation Complex Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012318:RNA Polymerase I / Q000378:metabolism*; D012335:RNA, Ribosomal / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D004611:Ellipticines; D004791:Enzyme Inhibitors; D035463:Pol1 Transcription Initiation Complex Proteins; D012335:RNA, Ribosomal; D012318:RNA Polymerase I; D001973:Bromodeoxyuridine