RSK inhibitor BI-D1870 inhibits acute myeloid leukemia cell proliferation by targeting mitotic exit.

Hee-Don Chae,Benedetta Accordi,Minyoung Youn,Nathan Sumarsono,Terzah M Horton,Kara L Davis,Martina Pigazzi,Ritika Dutta,Bruce Tiu,Steven M Kornblau,Min Huang,Kathleen M Sakamoto,Fieke W Hoff,Valentina Serafin,Norman J Lacayo

doi:10.18632/oncotarget.27630

Abstract

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.

Highlights

Acute myeloid leukemia (AML) is a genetically and phenotypically heterogeneous hematologic malignancy characterized by the accumulation of immature myeloid blasts with resultant peripheral blood cytopenia [1, 2]
CDC25C phosphatase activity is critical for the dephosphorylation at T14 and Y15 and subsequent activation of CDC2 during mitosis progression [35]
We demonstrated that Ribosomal S6 Kinase (RSK) is overexpressed and hyperactivated in AML, and that high levels confer an adverse prognosis, suggesting RSK inhibition as a potential therapeutic target in AML

Summary

Introduction

Acute myeloid leukemia (AML) is a genetically and phenotypically heterogeneous hematologic malignancy characterized by the accumulation of immature myeloid blasts with resultant peripheral blood cytopenia [1, 2]. The ERK phosphorylation site is conserved across the four vertebrate RSK isoforms RSK1 (RPS6KA1), RSK2 (RPS6KA3), RSK3 (RPS6KA2), and RSK4 (RPS6KA6). RSK activity is involved in numerous signaling pathways of cellular proliferation, survival, and migration through the phosphorylation of a wide range of targets, including tuberous sclerosis complex-1/2 (TSC1/2), membrane-associated tyrosineand threonine-specific CDC2 inhibitory kinase-1 (MYT1), CDC25, p27KIP1, cAMP Responsive Element Binding Protein, Bcl-2-associated death promoter (BAD), and death-associated protein kinase (DAPK) [9,10,11,12]

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Results

Conclusion