A novel immunosuppressive agent FTY720 induced Akt dephosphorylation in leukemia cells
A novel immunosuppressive agent FTY720 induced Akt dephosphorylation in leukemia cells
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DOI：
10.1038/sj.bjp.0705182
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发表时间：
2003-04-01
影响因子：
7.3
通讯作者：
Shinomiya, T
中科院分区：
文献类型：
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作者：
Matsuoka, Y;Nagahara, Y;Shinomiya, T
1我们以前的研究表明，免疫抑制剂FTY 720主要诱导某些类型的癌细胞中与Bcl-2相关的凋亡，因为Bcl-2过表达阻止了FTY 720诱导的凋亡刺激。FTY 720还可诱导G 0/G1期细胞阻滞。本研究进一步检查了细胞内信号激酶与FTY 720诱导的人T细胞白血病相关的细胞凋亡之间的相关性。2人T细胞白血病Jurkat暴露于FTY 720。Akt的去磷酸化以时间和浓度依赖性方式发生。FTY 720还诱导Bad（Ser（136））和核糖体p70 S6激酶（p70（S6 k））（Thr（389））去磷酸化。3 FTY 720诱导Akt去磷酸化不是因为Akt上游磷脂酰肌醇3 '-激酶（PI 3-kinase）途径抑制。4 FTY 720还诱导人B细胞白血病BALL-1中Akt去磷酸化。BALL-1细胞对FTY 720诱导的凋亡具有抵抗性。5冈田酸（OA）抑制FTY 720诱导的Akt和p70 S6 k去磷酸化，表明FTY 720促进Ser/Thr蛋白磷酸酶（PP）活性。6 OA部分抑制FTY 720诱导的caspase-3激活。7在暴露于FTY 720的细胞中，PP 2A或PP 2A样磷酸酶被暂时激活。此外，FTY 720激活纯化的PP 2A（ABC）。8总体而言，结果表明FTY 720激活PP 2A或PP 2A样磷酸酶和去磷酸化Akt途径因子，导致通过线粒体的细胞凋亡增强。
1 Our previous studies revealed that the immunosuppressive agent, FTY720, mainly induces mitochondria-involved apoptosis in some types of cancer cells, since Bcl-2 overexpression prevents the FTY720-induction of apoptotic stimuli. Furthermore, FTY720 induces G0/G1 cell cycle arrest. The present study further examines the correlation between intracellular signaling kinases with FTY720-induced mitochondria-involved apoptosis.2 Human T cell leukemia Jurkat was exposed to FTY720. Dephosphorylation of Akt occurred in a time- and concentration-dependent manner. FTY720 also induced Bad (Ser(136)) and ribosomal p70S6 kinase (p70(S6k)) (Thr(389)) dephosphorylation.3 FTY720-induced Akt dephosphorylation was not because of Akt upstream phosphatidylinositol 3'-kinase (PI 3-kinase) pathway inhibition.4 FTY720 also induced Akt dephosphorylation in human B cell leukemia BALL-1. BALL-1 cells were resistant to FTY720-induced apoptosis.5 Okadaic acid (OA) inhibited the FTY720-induced dephosphorylation of Akt and p70S6k, suggesting that FTY720 promotes Ser/Thr protein phosphatase (PP) activity.6 OA partially inhibited FTY720-induced caspase-3 activation.7 PP2A or PP2A-like phosphatase was temporarily activated in cells exposed to FTY720. In addition, FTY720 activated purified PP2A (ABC).8 Overall, the results suggest that FTY720 activated PP2A or PP2A-like phosphatase and dephosphorylated Akt pathway factors resulting in the enhancement of apoptosis via mitochondria.