title: Wogonin and related natural flavones are inhibitors of CDK9 that induce apoptosis in cancer cells by transcriptional suppression of Mcl-1.
abstract: The wogonin-containing herb Scutellaria baicalensis has successfully been used for curing various diseases in traditional Chinese medicine. Wogonin has been shown to induce apoptosis in different cancer cells and to suppress growth of human cancer xenografts in vivo. However, its direct targets remain unknown. In this study, we demonstrate for the first time that wogonin and structurally related natural flavones, for example, apigenin, chrysin and luteolin, are inhibitors of cyclin-dependent kinase 9 (CDK9) and block phosphorylation of the carboxy-terminal domain of RNA polymerase II at Ser(2). This effect leads to reduced RNA synthesis and subsequently rapid downregulation of the short-lived anti-apoptotic protein myeloid cell leukemia 1 (Mcl-1) resulting in apoptosis induction in cancer cells. We show that genetic inhibition of Mcl-1 or CDK9 expression by siRNA is sufficient to mimic flavone-induced apoptosis. Pull-down and in silico docking studies demonstrate that wogonin directly binds to CDK9, presumably to the ATP-binding pocket. In contrast, wogonin does not inhibit CDK2, CDK4 and CDK6 at doses that inhibit CDK9 activity. Furthermore, we show that wogonin preferentially inhibits CDK9 in malignant compared with normal lymphocytes. Thus, our study reveals a new mechanism of anti-cancer action of natural flavones and supports CDK9 as a therapeutic target in oncology.
authors.affiliation: Tumor Immunology Program (D030), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Polier
authors.forename: J
authors.initials: J
authors.lastname: Ding
authors.forename: B V
authors.initials: BV
authors.lastname: Konkimalla
authors.forename: D
authors.initials: D
authors.lastname: Eick
authors.forename: N
authors.initials: N
authors.lastname: Ribeiro
authors.forename: R
authors.initials: R
authors.lastname: Köhler
authors.forename: M
authors.initials: M
authors.lastname: Giaisi
authors.forename: T
authors.initials: T
authors.lastname: Efferth
authors.forename: L
authors.initials: L
authors.lastname: Desaubry
authors.forename: P H
authors.initials: PH
authors.lastname: Krammer
authors.forename: M
authors.initials: M
authors.lastname: Li-Weber
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D001665:Binding Sites; D045744:Cell Line, Tumor; D003198:Computer Simulation; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D044950:Flavanones / Q000627:therapeutic use / Q000633:toxicity*; D047309:Flavones / Q000627:therapeutic use / Q000633:toxicity*; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012319:RNA Polymerase II / Q000037:antagonists & inhibitors / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D031364:Scutellaria baicalensis / Q000737:chemistry; D014158:Transcription, Genetic
chemical_list: D000970:Antineoplastic Agents; D044950:Flavanones; D047309:Flavones; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D042863:Cyclin-Dependent Kinase 9; D012319:RNA Polymerase II; C085514:wogonin