Combined effects on leukemia cell growth by targeting sphingosine kinase 1 and sirtuin 1 signaling.

Abstract

Targeting multiple signaling pathways is a potential novel therapeutic strategy for the treatment of leukemias. Leukemia cells express high levels of sphingosine kinase 1 (Sphk1) and sirtuin 1 (SIRT1). However, to the best of our knowledge, their interaction and potential synergistic inhibitory effects on the growth and survival of leukemia cells have not been investigated. The present study revealed the role of the Sphk1/S1P/SIRT1 axis in K562, KCL22 and TF1 cells and hypothesized that the inhibition of Sphk1 and SIRT1 had synergistic effects on the growth and survival of leukemia cells. Cell viability was tested using a Cell Counting Kit-8 assay and cell colony forming assay. Cell apoptosis was detected using Annexin V-APC/PI staining. The stages of the cell cycle were measured using PI staining. Protein levels were measured by western blotting. Treatment of leukemia cells with S1P resulted in the upregulation of SIRT1 expression, whereas inhibition of Sphk1 induced SIRT1 downregulation in leukemia cells. Both SKI-II and EX527 actively suppressed growth, blocked cell cycle progression and induced apoptosis of leukemia cells. Furthermore, inhibition of Sphk1 and SIRT1 exhibited suppressive effects on the growth and survival of leukemia cells. Notably, the inhibition of Sphk1 and SIRT1 suppressed cell growth and induced apoptosis of T-315I mutation-harboring cells. Additionally, treatment with SKI-II and EX527 suppressed the ERK and STAT5 pathways in leukemia cells. These data indicated that targeting the Sphk1/S1P/SIRT1 axis may be a novel therapeutic strategy for the treatment of leukemia.