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- Title
Pharmacologic targeting of the P-TEFb complex as a therapeutic strategy for chronic myeloid leukemia.
- Authors
Qing, Yingjie; Wang, Xiangyuan; Wang, Hongzheng; Hu, Po; Li, Hui; Yu, Xiaoxuan; Zhu, Mengyuan; Wang, Zhanyu; Zhu, Yu; Xu, Jingyan; Guo, Qinglong; Hui, Hui
- Abstract
Background: The positive transcription elongation factor b (P-TEFb) kinase activity is involved in the process of transcription. Cyclin-dependent kinase 9 (CDK9), a core component of P-TEFb, regulates the process of transcription elongation, which is associated with differentiation and apoptosis in many cancer types. Wogonin, a natural CDK9 inhibitor isolated from Scutellaria baicalensis. This study aimed to investigate the involved molecular mechanisms of wogonin on anti- chronic myeloid leukemia (CML) cells. Materials and methods: mRNA and protein levels were analysed by RT-qPCR and western blot. Flow cytometry was used to assess cell differentiation and apoptosis. Cell transfection, immunofluorescence analysis and co-immunoprecipitation (co-IP) assays were applied to address the potential regulatory mechanism of wogonin. KU-812 cells xenograft NOD/SCID mice model was used to assess and verify the mechanism in vivo. Results: We reported that the anti-CML effects in K562, KU-812 and primary CML cells induced by wogonin were regulated by P-TEFb complex. We also confirmed the relationship between CDK9 and erythroid differentiation via knockdown the expression of CDK9. For further study the mechanism of erythroid differentiation induced by wogonin, co-IP experiments were used to demonstrate that wogonin increased the binding between GATA-1 and FOG-1 but decreased the binding between GATA-1 and RUNX1, which were depended on P-TEFb. Also, wogonin induced apoptosis and decreased the mRNA and protein levels of MCL-1 in KU-812 cells, which is the downstream of P-TEFb. In vivo studies showed wogonin had good anti-tumor effects in KU-812 xenografts NOD/ SCID mice model and decreased the proportion of human CD45+ cells in spleens of mice. We also verified that wogonin exhibited anti-CML effects through modulating P-TEFb activity in vivo. Conclusions: Our study indicated a special mechanism involving the regulation of P-TEFb kinase activity in CML cells, providing evidences for further application of wogonin in CML clinical treatment. 8GofEJwEVPixrLqaXtLiT8 Video Abstract
- Subjects
CHRONIC myeloid leukemia; ANIMAL disease models; LABORATORY mice; CELL differentiation; CHINESE skullcap
- Publication
Cell Communication & Signaling, 2021, Vol 19, Issue 1, p1
- ISSN
1478-811X
- Publication type
Article
- DOI
10.1186/s12964-021-00764-5