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Wogonin and related natural flavones are inhibitors of CDK9 that induce apoptosis in cancer cells by transcriptional suppression of Mcl-1.
Cell Death Dis. 2:e182 (2011)
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.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
anti-cancer drug; apoptosis; CDK9; Mcl-1; transcription; RNA-POLYMERASE-II; BREAST-CANCER; IN-VITRO; DOWN-REGULATION; TUMOR-GROWTH; PHOSPHORYLATION; VIVO; SCUTELLARIA; MECHANISM; PROGRESS
ISSN (print) / ISBN
2041-4889
e-ISSN
2041-4889
Journal
Cell Death & Disease
Quellenangaben
Volume: 2,
Article Number: e182
Publisher
Nature Publishing Group
Non-patent literature
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Reviewing status
Peer reviewed