Potteck Henrik, Nieuwenhuis Barbara, Lüth Anja, van der Giet Markus, Kleuser Burkhard
Faculty of Mathematics and Natural Science, Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.
Cell Physiol Biochem. 2010;26(1):67-78. doi: 10.1159/000315107. Epub 2010 May 18.
FTY720, a synthetic compound produced by modification of a metabolite from Isaria sinclairii, is known as a unique immunosuppressive agent that exerts its activity by inhibiting lymphocyte egress from secondary lymphoid tissues. FTY720 is phosphorylated in vivo by sphingosine kinase 2 to FTY720-phosphate (FTY720-P), which acts as a potent sphingosine-1-phosphate (S1P) receptor agonist. Despite its homology to S1P, which exerts antiapoptotic actions in different cells, FTY720 has also been reported to be able to induce apoptosis in a variety of cells.
Therefore, we investigated the action of both, FTY720 and its phosphorylated version FTY720-P, on apoptosis. Moreover, signalling pathways of apoptosis in response to FTY720 and FTY720-P were examined.
Although FTY720 acts apoptotic at micromolar concentrations in human fibroblasts the phosphorylated compound FTY720-P possesses a pronounced antiapoptotic effect counteracting FTY720-induced programmed cell death. Interestingly, none of the classical antiapoptotic pathways like MAP kinases, Akt or mTOR play a role in the protective role of FTY720-P. Most important, we identified that the S1P(3) receptor subtype is involved in the antiapoptotic action of FTY720-P leading to an increased phosphorylation of Bcl-2 and changes in the mitochondrial membrane potential.
FTY720是一种通过对蝉拟青霉代谢产物进行修饰而产生的合成化合物，是一种独特的免疫抑制剂，通过抑制淋巴细胞从次级淋巴组织中逸出发挥其活性。FTY720在体内被鞘氨醇激酶2磷酸化为磷酸化FTY720（FTY720-P），后者作为一种有效的1-磷酸鞘氨醇（S1P）受体激动剂。尽管FTY720与在不同细胞中发挥抗凋亡作用的S1P具有同源性，但也有报道称FTY720能够诱导多种细胞凋亡。
因此，我们研究了FTY720及其磷酸化形式FTY720-P对细胞凋亡的作用。此外，还检测了FTY720和FTY720-P诱导的细胞凋亡信号通路。
尽管FTY720在微摩尔浓度下对人成纤维细胞具有凋亡作用，但磷酸化化合物FTY720-P具有明显的抗凋亡作用，可抵消FTY720诱导的程序性细胞死亡。有趣的是，MAP激酶、Akt或mTOR等经典抗凋亡途径均未参与FTY720-P的保护作用。最重要的是，我们发现S1P(3)受体亚型参与了FTY720-P的抗凋亡作用，导致Bcl-2磷酸化增加和线粒体膜电位改变。
