Wogonin and related natural flavones are inhibitors of CDK9 that induce apoptosis in cancer cells by transcriptional suppression of Mcl-1
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- G Polier
- J Ding
- BV Konkimalla
- D Eick
- N Ribeiro
- R Koehler
- M Giaisi
- T Efferth
- L Desaubry
- PH Krammer
- M Li-Weber
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000293215600004&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1038/cddis.2011.66
- Externe Identifier
- Clarivate Analytics Document Solution ID: 798NN
- PubMed Identifier: 21776020
- ISSN
- 2041-4889
- Zeitschrift
- CELL DEATH & DISEASE
- Schlüsselwörter
- anti-cancer drug
- apoptosis
- CDK9
- Mcl-1
- transcription
- Artikelnummer
- ARTN e182
- Datum der Veröffentlichung
- 2011
- Status
- Published
- Titel
- Wogonin and related natural flavones are inhibitors of CDK9 that induce apoptosis in cancer cells by transcriptional suppression of Mcl-1
- Sub types
- Article
- Ausgabe der Zeitschrift
- 2
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Autoren
- G Polier
- J Ding
- BV Konkimalla
- D Eick
- N Ribeiro
- R Köhler
- M Giaisi
- T Efferth
- L Desaubry
- PH Krammer
- M Li-Weber
- DOI
- 10.1038/cddis.2011.66
- eISSN
- 2041-4889
- Ausgabe der Veröffentlichung
- 7
- Zeitschrift
- Cell Death & Disease
- Sprache
- en
- Online publication date
- 2011
- Paginierung
- e182 - e182
- Status
- Published online
- Herausgeber
- Springer Science and Business Media LLC
- Herausgeber URL
- http://dx.doi.org/10.1038/cddis.2011.66
- Datum der Datenerfassung
- 2023
- Titel
- Wogonin and related natural flavones are inhibitors of CDK9 that induce apoptosis in cancer cells by transcriptional suppression of Mcl-1
- Ausgabe der Zeitschrift
- 2
Data source: Crossref
- 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.
- Addresses
- Tumor Immunology Program (D030), German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Autoren
- G Polier
- J Ding
- BV Konkimalla
- D Eick
- N Ribeiro
- R Köhler
- M Giaisi
- T Efferth
- T Efferth
- L Desaubry
- PH Krammer
- M Li-Weber
- DOI
- 10.1038/cddis.2011.66
- eISSN
- 2041-4889
- Externe Identifier
- PubMed Identifier: 21776020
- PubMed Central ID: PMC3199715
- Open access
- true
- ISSN
- 2041-4889
- Zeitschrift
- Cell death & disease
- Schlüsselwörter
- Cell Line, Tumor
- Humans
- Scutellaria baicalensis
- Neoplasms
- Flavanones
- Flavones
- RNA Polymerase II
- Proto-Oncogene Proteins c-bcl-2
- RNA, Small Interfering
- Antineoplastic Agents
- Apoptosis
- Transcription, Genetic
- RNA Interference
- Binding Sites
- Protein Structure, Tertiary
- Phosphorylation
- Computer Simulation
- Cyclin-Dependent Kinase 9
- Myeloid Cell Leukemia Sequence 1 Protein
- Sprache
- eng
- Medium
- Electronic
- Online publication date
- 2011
- Open access status
- Open Access
- Paginierung
- e182
- Datum der Veröffentlichung
- 2011
- Status
- Published
- Publisher licence
- CC BY-NC-ND
- Datum der Datenerfassung
- 2011
- Titel
- Wogonin and related natural flavones are inhibitors of CDK9 that induce apoptosis in cancer cells by transcriptional suppression of Mcl-1.
- Sub types
- Research Support, Non-U.S. Gov't
- research-article
- Journal Article
- Ausgabe der Zeitschrift
- 2
Files
https://www.nature.com/articles/cddis201166.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21776020/pdf/?tool=EBI https://europepmc.org/articles/PMC3199715?pdf=render
Data source: Europe PubMed Central
- 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.
- Autoren
- G Polier
- J Ding
- BV Konkimalla
- D Eick
- N Ribeiro
- R Köhler
- M Giaisi
- T Efferth
- L Desaubry
- PH Krammer
- M Li-Weber
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/21776020
- DOI
- 10.1038/cddis.2011.66
- eISSN
- 2041-4889
- Externe Identifier
- PubMed Central ID: PMC3199715
- Ausgabe der Veröffentlichung
- 7
- Zeitschrift
- Cell Death Dis
- Schlüsselwörter
- Antineoplastic Agents
- Apoptosis
- Binding Sites
- Cell Line, Tumor
- Computer Simulation
- Cyclin-Dependent Kinase 9
- Flavanones
- Flavones
- Humans
- Myeloid Cell Leukemia Sequence 1 Protein
- Neoplasms
- Phosphorylation
- Protein Structure, Tertiary
- Proto-Oncogene Proteins c-bcl-2
- RNA Interference
- RNA Polymerase II
- RNA, Small Interfering
- Scutellaria baicalensis
- Transcription, Genetic
- Sprache
- eng
- Country
- England
- Paginierung
- e182
- PII
- cddis201166
- Datum der Veröffentlichung
- 2011
- Status
- Published online
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2011
- Titel
- Wogonin and related natural flavones are inhibitors of CDK9 that induce apoptosis in cancer cells by transcriptional suppression of Mcl-1.
- Sub types
- Journal Article
- Research Support, Non-U.S. Gov't
- Ausgabe der Zeitschrift
- 2
Data source: PubMed
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- Property of