title: Triptolide is an inhibitor of RNA polymerase I and II-dependent transcription leading predominantly to down-regulation of short-lived mRNA.
abstract: Triptolide, a natural product extracted from the Chinese plant Tripterygium wilfordii, possesses antitumor properties. Despite numerous reports showing the proapoptotic capacity and the inhibition of NF-kappaB-mediated transcription by triptolide, the identity of its cellular target is still unknown. To clarify its mechanism of action, we further investigated the effect of triptolide on RNA synthesis in the human non-small cell lung cancer cell line A549. Triptolide inhibited both total RNA and mRNA de novo synthesis, with the primary action being on the latter pool. We used 44K human pan-genomic DNA microarrays and identified the genes primarily affected by a short treatment with triptolide. Among the modulated genes, up to 98% are down-regulated, encompassing a large array of oncogenes including transcription factors and cell cycle regulators. We next observed that triptolide induced a rapid depletion of RPB1, the RNA polymerase II main subunit that is considered a hallmark of a transcription elongation blockage. However, we also show that triptolide does not directly interact with the RNA polymerase II complex nor does it damage DNA. We thus conclude that triptolide is an original pharmacologic inhibitor of RNA polymerase activity, affecting indirectly the transcription machinery, leading to a rapid depletion of short-lived mRNA, including transcription factors, cell cycle regulators such as CDC25A, and the oncogenes MYC and Src. Overall, the data shed light on the effect of triptolide on transcription, along with its novel potential applications in cancers, including acute myeloid leukemia, which is in part driven by the aforementioned oncogenic factors.
authors.affiliation: Centre de Recherche en Oncologie Expérimentale, Institut de Recherche Pierre Fabre, 3 rue des satellites, BP94244, Toulouse Cedex 4, 31432 France. stephane.vispe@pierre-fabre.com
authors.forename: Stéphane
authors.initials: S
authors.lastname: Vispé
authors.forename: Luc
authors.initials: L
authors.lastname: DeVries
authors.forename: Laurent
authors.initials: L
authors.lastname: Créancier
authors.forename: Jérome
authors.initials: J
authors.lastname: Besse
authors.forename: Sophie
authors.initials: S
authors.lastname: Bréand
authors.forename: David J
authors.initials: DJ
authors.lastname: Hobson
authors.forename: Jesper Q
authors.initials: JQ
authors.lastname: Svejstrup
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Annereau
authors.forename: Didier
authors.initials: D
authors.lastname: Cussac
authors.forename: Charles
authors.initials: C
authors.lastname: Dumontet
authors.forename: Nicolas
authors.initials: N
authors.lastname: Guilbaud
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Barret
authors.forename: Christian
authors.initials: C
authors.lastname: Bailly
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004224:Diterpenes / Q000737:chemistry* / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects*; D004852:Epoxy Compounds / Q000737:chemistry / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D010616:Phenanthrenes / Q000737:chemistry* / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012318:RNA Polymerase I / Q000037:antagonists & inhibitors*; D012319:RNA Polymerase II / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D004224:Diterpenes; C494112:ELK1 protein, human; D004852:Epoxy Compounds; D010616:Phenanthrenes; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D016159:Tumor Suppressor Protein p53; D050807:ets-Domain Protein Elk-1; C001899:triptolide; D012319:RNA Polymerase II; D012318:RNA Polymerase I