Implications of sphingosine kinase 1 expression level for the cellular sphingolipid rheostat: relevance as a marker for daunorubicin sensitivity of leukemia cells
Implications of sphingosine kinase 1 expression level for the cellular sphingolipid rheostat: relevance as a marker for daunorubicin sensitivity of leukemia cells
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DOI：
10.1007/s12185-008-0052-0
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发表时间：
2008-04-01
影响因子：
2.1
通讯作者：
Murate, T.
中科院分区：
文献类型：
--
作者：
Sobue, S.;Nemoto, S.;Murate, T.
我们最近报道了在骨髓增生异常综合征和急性白血病中鞘氨醇激酶1（SPHK 1）基因表达增加和中性鞘磷脂酶2（NSMase 2）基因表达减少。这种改变被认为改变了细胞鞘脂代谢物;然而，当使用16种不同的白血病细胞系来分析基因表达与对柔红霉素（DA）的化疗敏感性之间的关系时，观察到柔红霉素（DA）-IC 50与SPHK 1信使之间的正相关性，而DA-IC 50与NSMase 2信使之间的正相关性不存在。使用具有最高或最低SPHK 1表达的两种细胞系，通过液相色谱/质谱法定量细胞神经酰胺和1-磷酸鞘氨醇（S1 P）。增加神经酰胺中观察到DA敏感，但没有在DA耐药细胞系用低剂量的DA处理。DA处理后，S1 P下降更多的敏感细胞系比耐药细胞系。SPHK抑制剂恢复DA抗性细胞的DA敏感性。通过过表达或使用siRNA调节SPHK 1基因表达影响代表性细胞系的DA敏感性。结果清楚地表明，SPHK 1是一个很好的标志物，预测DA敏感性的白血病细胞和一个潜在的治疗靶点与SPHK 1高表达的白血病，并建议鞘脂变阻器DA诱导的细胞毒性中发挥重要作用。
We recently reported increased sphingosine kinase 1 (SPHK1) and decreased neutral sphingomyelinase 2 (NSMase2) gene expression in myelodysplastic syndromes and acute leukemia. This alteration is supposed to change the cellular sphingolipid metabolites; however, positive correlations were observed between daunorubicin (DA)-IC50 and the SPHK1 message but not between DA-IC50 and NSMase2 messages, when 16 different leukemia cell lines were used to analyze the relationship between gene expressions and chemosensitivity against DA. Using two cell lines with either the highest or 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 lines than in resistant cell lines. A SPHK inhibitor recovered the DA sensitivity of DA-resistant cells. The modulation of SPHK1 gene expression by either overexpression or using siRNA affected the DA sensitivity of representative cell lines. Results clearly show that SPHK1 is both a good marker to predict the DA sensitivity of leukemia cells and a potential therapeutic target for leukemia with high SPHK1 expression, and suggest that the sphingolipid rheostat plays a significant role in DA-induced cytotoxicity.