Aberrant expression of sphingosine kinase and its pathological significance of malignant tumors and neuronal degenerative diseases

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1.Sphingolipid metabolic enzymes gene expression of myelodysplastic syndrome (MDS) and acute leukemia was measured by quantitative RT-PCR method. It was shown that sphingosine kinase 1 (SPHK1) was increased in high risk MDS and acute leukemia and that neutral sphingomyelinase 2 (NSMase2) was decreased in bone marrow samples from high risk MDS and acute leukemia Using established leukemia cell lines, further analysis was performed. It was revealed that SPHK1 message, SPHK1 protein and SPHK enzyme activity were well correlated with IC50 of anti-cancer drug, daunorubicin (DA) . Sphingolipid metabolites were measured by LC/MS-MS (liquid column chromatography followed by tandem mass spectrometry) . DA treatment modulated each sphingolipid metabolite level. There was a remarkable heterogeneity of IC50 of DA as well as SPHK expression level. With low dose of DA, DA-sensitive cell lines showed remarkable increase of ceramides as well as decrease of sphingosine 1-phosphate (S1P) compared with DA-resistant cell lines. The ratio of ceramide/S1P was changed greatly with IC50 dose of DA. Our results showed, for the first time, that sphingolipid rheostat model proposed by Spiegel, et. al. can be applied in hematological malignancies.2.Using a GDNF (glial cell line derived neurotrophic factor) -responsive neuroblastoma cell line, TGW, we showed that SPHK1 was increased with GDNF and that the response was mediated through the GDNF receptor, RET. Mutated REF gene was recognized as the pathogenesis of MEN2 type tumors. We also proved that SPHK1 gene expression was increased in MEN2 type tumors and that increased SPHK1 gene expression was involved in its oncogenesis.