sphingosine-1-phosphate and Leukemia--Myeloid

In this chapter, we review the latest developments concerning the role of sphingosine 1-phosphate (S1P) in cancer. Particular focus is paid to the role of sphingosine kinases 1 and 2, S1P lyase and S1P-dependent signalling networks in both solid tumours and haematological cancer. The potential of this S1P-dependent pathophysiology as a therapeutic target for the treatment of cancer is also discussed.

Topics: Aldehyde-Lyases; Animals; Antineoplastic Agents; Humans; Leukemia, Myeloid; Lysophospholipids; Molecular Targeted Therapy; Multiple Myeloma; Neoplasms; Oncogenes; Phosphotransferases (Alcohol Group Acceptor); Protein Kinase Inhibitors; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine

To explore the effects of resveratrol in a human myelogenous leukemia cell line K562 and its potential molecular mechanisms. The anti-proliferation effect of resveratrol-induced apoptosis on K562 cells were detected using MTT assay. Western blotting was performed for detecting changes of SphK1 expression in total cell protein and membrane/cytosol protein in K562 cells respectively after exposure to resveratrol. A biochemical assay was used to measure the activity of SphK after treatment of resveratrol, and then S1P and ceramide levels were examined using ELISA kits. Hochest 33258 staining and flow cytometry were applied to detect the apoptosis condition of K562 cells treated with resveratrol. Resveratrol inhibited the proliferation and induced apoptosis in K562 cells in a dose and time-dependent manner. Western blotting revealed that resveratrol did not affect total SphK1 expression level in K562 cells, but significantly changed the translocation of SphK1, the membrane SphK1 was decreased while cytosol SphK1 level was elevated. The activity of SphK1 in resveratrol treated groups was decreased compared to control group with a significant decrease of S1P and increase of ceramide level. Furthermore, Hoechst 33258 staining and Annexin V-FITC analysis confirmed the notable apoptotic effect of resveratrol in its anti-leukemia process. Resveratrol-induced proliferation inhibition of K562 cells might be mediated through its modulation activity of SphK1 pathway by regulating S1P and ceramide levels, which then affected the proliferation and apoptosis process of leukemia cells. SphK1/S1P pathway represents a target of resveratrol in human leukemia.

Topics: Annexin A5; Antineoplastic Agents; Apoptosis; Cell Membrane; Cell Proliferation; Ceramides; Cytosol; Dose-Response Relationship, Drug; Humans; K562 Cells; Leukemia, Myeloid; Lysophospholipids; Phosphotransferases (Alcohol Group Acceptor); Protein Transport; Resveratrol; Signal Transduction; Sphingosine; Stilbenes; Time Factors

Sphingosine-1-phosphate (SPP), a metabolite of sphingolipids, has been implicated as a second messenger in cell growth regulation and signal transduction via calcium mobilization from internal stores. This study shows that SPP mobilizes intracellular calcium in U937 cells and demonstrates for the first time the ability of SPP to activate the transcription factor NF-kappa B in these cells. Furthermore, calcium release from the internal stores by thapsigargin (TG), an inhibitor of the endoplasmic reticulum Ca2+ pump, was associated with activation of NF-kappa B. Moreover, we have shown that while an intracellular calcium chelator BAPTA/AM was able to inhibit both SPP- and TG-induced NF-kappa B activation, it had no effect on TNF-induced NF-kappa B activation. In addition, SPP-induced NF-kappa B activation was blocked both by cyclosporin A, known to inhibit calcineurin phosphatase activity, and by the antioxidant butylated hydroxyanisole. These observations suggest that intracellular calcium mobilization is required for SPP-induced NF-kappa B activation, which may involve calcineurin- and redox-dependent mechanisms.

Topics: Antioxidants; Butylated Hydroxyanisole; Calcium; Chelating Agents; Cyclosporine; DNA Probes; Egtazic Acid; Electrophoresis, Polyacrylamide Gel; Enzyme Inhibitors; Fluorescent Dyes; Genes, Reporter; Humans; Indoles; Leukemia, Myeloid; Luciferases; Lysophospholipids; NF-kappa B; Sphingolipids; Sphingosine; Thapsigargin; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha