Min Kyoung-Jin, Kwon Taeg Kyu
Department of Immunology, School of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-Gu, Daegu 42601, Korea.
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, 80 Chembok-ro, Dong-gu, Daegu 41061, Korea.
Cancers (Basel). 2020 Nov 16;12(11):3388. doi: 10.3390/cancers12113388.
FTY720, a sphingosine-1-phosphate (S1P) receptor modulator, is a synthetic compound produced by the modification of a metabolite from . Here, we found that FTY720 induced non-apoptotic cell death in human glioma cells (U251MG, U87MG, and U118MG). FTY720 (10 µM) dramatically induced cytoplasmic vacuolation in glioma cells. However, FTY720-mediated vacuolation and cell death are not associated with autophagy. Genetic or pharmacological inhibition of autophagy did not inhibit FTY720-induced cell death. Herein, we detected that FTY720-induced cytoplasmic vacuoles were stained with lysotracker red, and FTY720 induced lysosomal membrane permeabilization (LMP). Interestingly, cathepsin inhibitors (E64D and pepstatin A) and ectopic expression of heat shock protein 70 (HSP70), which is an endogenous inhibitor of LMP, markedly inhibited FTY720-induced cell death. Our results demonstrated that FTY720 induced non-apoptotic cell death via the induction of LMP in human glioma cells.
FTY720是一种鞘氨醇-1-磷酸（S1P）受体调节剂，是通过对一种代谢产物进行修饰而产生的合成化合物。在此，我们发现FTY720可诱导人胶质瘤细胞（U251MG、U87MG和U118MG）发生非凋亡性细胞死亡。FTY720（10 µM）可显著诱导胶质瘤细胞出现细胞质空泡化。然而，FTY720介导的空泡化和细胞死亡与自噬无关。自噬的基因或药理学抑制并未抑制FTY720诱导的细胞死亡。在此，我们检测到FTY720诱导的细胞质空泡被溶酶体追踪红染色，且FTY720诱导了溶酶体膜通透性增加（LMP）。有趣的是，组织蛋白酶抑制剂（E64D和胃蛋白酶抑制剂A）以及热休克蛋白70（HSP70）的异位表达（HSP70是LMP的内源性抑制剂）显著抑制了FTY720诱导的细胞死亡。我们的结果表明，FTY720通过诱导人胶质瘤细胞中的LMP而诱导非凋亡性细胞死亡。
