Sphingosine kinase 1 expression is involved in leukemogenesis and modulates cellular sphingolipid rheostat, which is a good predictive marker of daunorubicin sensitivity スフィンゴシンキナーゼ1発現の白血病化および抗癌剤ダウノルビシン感受性に対する影響

博士論文

It was reported that sphingosine kinase (SPHK) gene expression was increased in tumor tissues and that overexpression of SPHK1 in solid tumor cell lines was involved in anti-cancer drug resistance. Here, we reported the increase in sphingosine kinase 1 (SPHK1) and decrease in neutral sphingomyelinase 2 (NSMase2) gene expression in myelodysplastic syndromes and acute leukemia. This alteration is supposed to change the cellular sphingolipid rheostat and effects anti-cancer drug sensitivity. However, positive correlations were observed between daunorubicin (DA)-IC_50 and the SPHK1 message but not between DA-IC_50 and NSMase2 messages, when 16 different leukemia cell lines were used to analyze the relationship between gene expressions and the chemosensitivity against DA. Using two cell lines with either the highest or the lowest SPHK1 expression, cellular ceramides and sphingosine 1-phosphate (S1P) were quantified by liquid chromatography/mass spectrometry. Increased ceramide was observed in DA-sensitive, but not in DA-resistant cell lines treated with low doses of DA. Upon DA treatment, S1P decreased more in the sensitive cell line than in the resistant cell lines. A SPHK inhibitor recovered the DA-sensitivity of DA-resistant cells. Furthermore, the modulation of SPHK1 gene expression by either overexpression or using siRNA affected the DA sensitivity of representative cell lines. Our results clearly show that the sphingolipid rheostat plays a significant role in DA-induced cytotoxicity of leukemia cells, and suggest that SPHK1 is both a good marker to predict DA-sensitivity of leukemia cells and a potential therapeutic target for leukemia with high SPHK1 expression.

名古屋大学博士学位論文 学位の種類:博士（医療技術学）（課程） 学位授与年月日:平成20年3月25日