The involvement of sphingolipid metabolism in anti cancer drug sensitivity of malignant cells

在第一年，我们分析了GDNF处理神经细胞系TGW过程中GAP43表达的机制。我们的分析表明，GDNF通过RET受体诱导SPHK1的表达，随后S1P的分泌和S1P1/3受体的激活。我们进一步发现，GAP43的表达是由于CREB转录因子与GAP43 5‘-启动子区域结合增加所致。接下来，我们分析了全反式维甲酸(ATRA)对中性神经鞘磷脂酶2和中性神经酰胺酶的调节机制。我们的分析表明，激活的Sp1转录因子和降低的GATA2分别对处理后的MCF-7和SH-SY5Y细胞的变化做出了反应。第三年，我们分析了小鼠Friend细胞SPHK1高表达的机制。我们发现c-myb负责这种过度表达，化学诱导剂HMBA迅速降低SPHK1的表达，这至少是这种末端分化过程的部分原因。

In the first year, we analyzed the mechanism of GAP43 expression during GDNF treatment of a neuronal cel line, TGW. Our analysis revealed that GDNF induced SPHK1 expression through RET receptor, followed by S1P secretion and S1P1/3 receptor activation. We further found that GAP43 expression was due to the increased CREB transcription factor binding to the GAP43 5'-promoter region.Next, we analyzed the regulatory mechanism of neutral sphingomyelinase 2 and neutral ceramidase with all trans retinoid acid (ATRA). Our analysis revealed that activated Sp1 transcription factor and decreased GATA2 were responsive for the observed changes in treated MCF-7 and SH-SY5Y cells, respectively.In the third year, we analyzed the mechanism of high SPHK1 expression of mouse Friend cells. We found that c-MYB is responsible for this overepression and that chemical inducer, HMBA, rapidly decreased SPHK1 expression, which is at least partially responsible for this terminal differentiation process.