sphingosine-kinase and Anemia

Current markers available for screening normal populations and for monitoring prostate cancer (PCa) treatment lack sensitivity and selectivity. Sphingosine-1-phosphate (S1P) is a circulating lipid second messenger involved in cell growth and migration, the immune response, angiogenesis, and malignant transformation.. Eighty-eight patients with localised, locally advanced, or metastatic PCa were recruited into this prospective single-centre study. Plasma S1P levels were measured and compared with age-matched controls with benign prostate hyperplasia (BPH) (n=110) or with young healthy males with the very small chance of having PCa foci (n=20).. Levels of circulating S1P were significantly higher in healthy subjects (10.36 ± 0.69 pmol per mg protein, P<0.0001) and patients with BPH (9.39 ± 0.75, P=0.0013) than in patients with PCa (6.89 ± 0.58, ANOVA, P=0.0019). Circulating S1P levels were an early marker of PCa progression to hormonal unresponsiveness and correlated with prostate-specific antigen (PSA) levels and lymph node metastasis. During the course of the study, nine patients have died of PCa. Importantly, their circulating S1P levels were significantly lower (5.11 ± 0.75) than in the surviving patients (7.02 ± 0.22, n=79, P=0.0439). Our data suggest that the decrease in circulating S1P during PCa progression may stem from a highly significant downregulation of erythrocyte sphingosine kinase-1 (SphK1) activity (2.14 ± 0.17 pmol per mg protein per minute in PCa patients vs 4.7 ± 0.42 in healthy individuals, P<0.0001), which may be a potential mechanism of cancer-induced anaemia.. This current study has provided a potential mechanism for cancer-related anaemia and the first evidence that plasma S1P and erythrocyte SphK1 activity are the potential markers for the diagnosis, monitoring, and predicating for PCa mortality.

Topics: Anemia; Biomarkers, Tumor; Cell Line, Tumor; Disease Progression; Early Detection of Cancer; Erythrocytes; Humans; Lysophospholipids; Male; Phosphotransferases (Alcohol Group Acceptor); Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms; Sphingosine

Sphingosine 1-phosphate (S1P), an abundant lipid mediator in plasma, regulates vascular and immune cells by activating S1P receptors. In this report, we investigated the mechanisms by which high plasma S1P levels are maintained in mice. We found that plasma S1P turns over rapidly with a half-life of approximately 15 minutes, suggesting the existence of a high-capacity biosynthetic source(s). Transplantation of bone marrow from wild-type to Sphk1(-/-)Sphk2(+/-) mice restored plasma S1P levels, suggesting that hematopoietic cells are capable of secreting S1P into plasma. However, plasma S1P levels were not appreciably altered in mice that were thrombocytopenic, anemic, or leukopenic. Surprisingly, reconstitution of Sphk1(-/-)Sphk2(+/-) bone marrow cells into wild-type hosts failed to reduce plasma S1P, suggesting the existence of an additional, nonhematopoietic source for plasma S1P. Adenoviral expression of Sphk1 in the liver of Sphk1(-/-) mice restored plasma S1P levels. In vitro, vascular endothelial cells, but not hepatocytes, secreted S1P in a constitutive manner. Interestingly, laminar shear stress downregulated the expression of S1P lyase (Sgpl) and S1P phosphatase-1 (Sgpp1) while concomitantly stimulating S1P release from endothelial cells in vitro. Modulation of expression of endothelial S1P lyase with small interfering RNA and adenoviral expression altered S1P secretion, suggesting an important role played by this enzyme. These data suggest that the vascular endothelium, in addition to the hematopoietic system, is a major contributor of plasma S1P.

Topics: Adenoviridae; Aldehyde-Lyases; Anemia; Animals; Antibodies, Monoclonal; Bone Marrow Cells; Bone Marrow Transplantation; Cell Line; Cell Line, Tumor; Cells, Cultured; Disease Models, Animal; Endothelial Cells; Endothelium, Vascular; Genetic Vectors; Half-Life; Humans; Leukopenia; Liver; Lysophospholipids; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Phenylhydrazines; Phosphoric Monoester Hydrolases; Phosphotransferases (Alcohol Group Acceptor); Platelet Glycoprotein GPIb-IX Complex; RNA Interference; RNA, Small Interfering; Sphingosine; Stress, Mechanical; Thrombocytopenia; Time Factors; Transduction, Genetic; Whole-Body Irradiation

Topics: Aldehyde-Lyases; Anemia; Animals; Antibodies, Monoclonal; Bone Marrow Cells; Disease Models, Animal; Endothelial Cells; Endothelium, Vascular; Half-Life; Humans; Leukopenia; Liver; Lysophospholipids; Membrane Proteins; Phenylhydrazines; Phosphoric Monoester Hydrolases; Phosphotransferases (Alcohol Group Acceptor); Platelet Glycoprotein GPIb-IX Complex; Research Design; Signal Transduction; Sphingosine; Stress, Mechanical; Thrombocytopenia; Time Factors