Sphingosine kinase 1 regulates the Akt/FOXO3a/Bim pathway and contributes to apoptosis resistance in glioma cells.
Sphingosine kinase 1 regulates the Akt/FOXO3a/Bim pathway and contributes to apoptosis resistance in glioma cells.
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鞘氨醇激酶 1 调节 Akt/FOXO3a/Bim 通路并有助于胶质瘤细胞的凋亡抵抗
DOI：
10.1371/journal.pone.0019946
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Li M
中科院分区：
文献类型：
--
作者：
Guan H;Song L;Cai J;Huang Y;Wu J;Yuan J;Li J;Li M
本研究的目的是探讨鞘氨醇激酶-1(SPHK1)在脑胶质瘤细胞中发挥抗凋亡作用的机制。我们在此报告，在体外和体内，SPHK1的异常调节改变了胶质瘤对细胞凋亡的敏感性。进一步的机制研究检测了Bcl2家族成员，包括Bcl2，Mcl-1，Bax和Bim在SPHK1过表达的胶质瘤细胞中的表达，发现只有促凋亡的Bim被SPHK1下调。此外，SPHK1还改变了胶质瘤细胞中Bim的转录水平。接下来，我们证实了SPHK1和Bim在原发胶质瘤标本中的表达之间的相关性。重要的是，SPHK1在胶质瘤细胞中的表达显著增加Akt活性和FOXO3a的磷酸化失活，从而导致Bim下调。药理学研究表明，SPHK1的这些作用依赖于磷脂酰肌醇3-激酶(PI3K)。此外，SPHK1对Akt/FOXO3a/Bim通路的影响可被SPHK1特异性RNA干扰或SPHK1抑制剂逆转。总之，我们的结果表明，调节Akt/FOXO3a/Bim通路可能是SPHK1保护胶质瘤细胞免受凋亡，从而参与胶质瘤发生的一种新机制。
The aim of this study was to investigate the mechanism through which Sphingosine kinase-1 (SPHK1) exerts its anti-apoptosis activity in glioma cancer cells. We here report that dysregulation of SPHK1 alters the sensitivity of glioma to apoptosis both in vitro and in vivo. Further mechanistic study examined the expression of Bcl-2 family members, including Bcl-2, Mcl-1, Bax and Bim, in SPHK1-overexpressing glioma cells and revealed that only pro-apoptotic Bim was downregulated by SPHK1. Moreover, the transcriptional level of Bim was also altered by SPHK1 in glioma cells. We next confirmed the correlation between SPHK1 and Bim expression in primary glioma specimens. Importantly, increasing SPHK1 expression in glioma cells markedly elevated Akt activity and phosphorylated inactivation of FOXO3a, which led to downregulation of Bim. A pharmacological approach showed that these effects of SPHK1 were dependent on phosphatidylinositol 3-kinase (PI3K). Furthermore, effects of SPHK1 on Akt/FOXO3a/Bim pathway could be reversed by SPHK1 specific RNA interference or SPHK1 inhibitor. Collectively, our results indicate that regulation of the Akt/FOXO3a/Bim pathway may be a novel mechanism by which SPHK1 protects glioma cells from apoptosis, thereby involved in glioma tumorigenesis.
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影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
FOXO转录因子直接激活BIM基因表达并促进交感神经元中的凋亡。
影响因子：
7.8
作者：
Gilley, Jonathan;Coffer, Paul J;Ham, Jonathan
通讯作者：
Ham, Jonathan
影响因子：
8
作者：
Essafi, A;de Mattos, SF;Lam, EWF
通讯作者：
Lam, EWF
癌蛋白 Bmi-1 通过激活 IKK-核因子-kappaB 通路，对神经胶质瘤细胞产生凋亡抵抗。
影响因子：
6
作者：
Li, Jun;Gong, Li-Yun;Li, Mengfeng
通讯作者：
Li, Mengfeng
影响因子：
11.4
作者：
Bonhoure, E.;Lauret, A.;Cuvillier, O.
通讯作者：
Cuvillier, O.