Objectives: The serine/threonine PIM protein kinases are critical regulators of tumorigenesis in multiple cancers. However, whether PIMs are potential therapeutic targets for treating B-cell acute lymphocytic leukemia (B-ALL) remains unclear. Therefore, here, PIM expression was detected in B-ALL patients and the effects of SMI-4a, a pan-PIM small molecule inhibitor, were investigated in B-ALL cells.
Methods: PIM1 and PIM2 expression in 26 newly diagnosed B-ALL cases was detected by real-time PCR and Western blot. B-ALL cells were treated with varied SMI-4a doses and the viability of treated cells was investigated using a cell-counting kit-8 (CCK-8) assay. Apoptosis and cell cycles were analyzed by flow cytometry. Western blot analysis was then used to explore the expression of apoptosis-related proteins and the JAK2/STAT3 pathway.
Results: PIM1 and 2 were overexpressed in B-ALL patients with high HO-1 level. SMI-4a induced decreases in PIMs and HO-1 expressions and inhibited B-ALL cell viability. Treatment with SMI-4a induced apoptosis by downregulating Bcl-2, upregulating Bax and other antiapoptotic proteins, and decreasing protein levels of p-JAK2 and p-STAT3. In addition, upregulation of HO-1 alleviated decrease in p-JAK2 and p-STAT3 expression, reduced SMI-4a-induced apoptosis of B-ALL cells, and influenced B-ALL cell survival.
Conclusions: PIMs were highly expressed in B-ALL patients. SMI-4a inhibited B-ALL proliferation and induced apoptosis via the HO-1-mediated JAK2/STAT3 pathway. SMI-4a might be applicable for treatment of B-ALL cells.
Keywords: Apoptosis; B-ALL; JAK2/STAT3; SMI-4a.
Copyright © 2019. Published by Elsevier Inc.