S1PR1 mediates anti-apoptotic/pro-proliferative processes in human acute myeloid leukemia cells

Abstract

Sphingosine-1-phosphate receptor 1 (S1PR1), the G protein-coupled receptor 1 of sphingosine 1-phosphate (S1P), is crucial in the progression of various types of solid tumor through the positive regulation of anti-apoptotic/pro-survival responses by S1P-S1PR1 signaling. However, the role of S1PR1 in the progression of human acute myeloid leukemia (AML) remains to be fully elucidated. In the present study, the correlation between the expression level of S1PR1 and the growth and apoptosis of human AML cells was investigated. Using overexpression and RNA interference knockdown assays, it was shown that the expression of S1PR1 in several human myeloid leukemia cell lines contributed to the suppression of cell apoptosis and promotion of cell proliferation. S1PR1 inhibited the expression level of B cell lymphoma-2-associated X protein, a mitochondrion-associated apoptosis promoter, and prevented caspase-3 cleavage, indicating that S1PR1 interfered with the mitochondrion-associated apoptotic processes in AML cells. In addition, the present study demonstrated that S1PR1 suppressed the generation of reactive oxygen species (ROS) in AML cells, and that the apoptosis mediated by the downregulation of S1PR1 was partially reversed by treatment with N-acetyl-L-cysteine, a ROS scavenging agent, suggesting that the S1PR1-induced resistance of cell apoptosis resulted, at least partially, from the suppression of ROS generation. Additionally, S1PR1 was able to interfere with the signaling of c-Jun N-terminal kinase, which may have also contribute dto the suppression of cell apoptosis. By contrast, extracellular signal-regulated kinase (ERK) signaling appeared to be positively modulated by the S1PR1-induced enhancement of mitogen-activated protein kinase (MAPK) kinase 1 (MKK1) activation, suggesting that S1PR1 may promote cell survival and proliferation through enhancing the activation of MKK1-ERK signaling. In conclusion, S1PR1 likely serves as an anti-apoptotic/pro-proliferative protein in AML cells through the inhibition of mitochondrion-associated apoptosis and ROS generation, and via the regulation of multiple MAPK signaling cascades.