RSK inhibitor BI-D1870 inhibits acute myeloid leukemia cell proliferation by targeting mitotic exit
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Hee-Don Chae1, Ritika Dutta1, Bruce Tiu1, Fieke W. Hoff2, Benedetta Accordi3, Valentina Serafin3, Minyoung Youn1, Min Huang1, Nathan Sumarsono1, Kara L. Davis1, Norman J. Lacayo1, Martina Pigazzi3, Terzah M. Horton4, Steven M. Kornblau5 and Kathleen M. Sakamoto1
1 Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
2 Department of Pediatric Oncology/Hematology, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
3 Department of Women’s and Children’s Health, Onco-Hematology Clinic, University of Padova, Padova, Italy
4 Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, TX, USA
5 Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
|Kathleen M. Sakamoto,||email:||email@example.com|
Keywords: acute myeloid leukemia; BI-D1870; RSK; vincristine; spindle assembly checkpoint
Received: March 11, 2020 Accepted: May 20, 2020 Published: June 23, 2020
The 90 kDa Ribosomal S6 Kinase (RSK) drives cell proliferation and survival in cancers, although its oncogenic mechanism has not been well characterized. Phosphorylated level of RSK (T573) was increased in acute myeloid leukemia (AML) patients and associated with poor survival. To examine the role of RSK in AML, we analyzed apoptosis and the cell cycle profile following treatment with BI-D1870, a potent inhibitor of RSK. BI-D1870 treatment increased the G2/M population and induced apoptosis in AML cell lines and patient AML cells. Characterization of mitotic phases showed that the metaphase/anaphase transition was significantly inhibited by BI-D1870. BI-D1870 treatment impeded the association of activator CDC20 with APC/C, but increased binding of inhibitor MAD2 to CDC20, preventing mitotic exit. Moreover, the inactivation of spindle assembly checkpoint or MAD2 knockdown released cells from BI-D1870-induced metaphase arrest. Therefore, we investigated whether BI-D1870 potentiates the anti-leukemic activity of vincristine by targeting mitotic exit. Combination treatment of BI-D1870 and vincristine synergistically increased mitotic arrest and apoptosis in acute leukemia cells. These data show that BI-D1870 induces apoptosis of AML cells alone and in combination with vincristine through blocking mitotic exit, providing a novel approach to overcoming vincristine resistance in AML cells.
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