Role of AKT kinase in sphingosine-induced apoptosis in human hepatoma cells
Role of AKT kinase in sphingosine-induced apoptosis in human hepatoma cells
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DOI：
10.1002/jcp.1108
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发表时间：
2001-08-01
影响因子：
5.6
通讯作者：
Hung, WC
中科院分区：
文献类型：
--
作者：
Chang, HC;Tsai, LH;Hung, WC
我们之前的工作表明，包括鞘氨醇、鞘氨醇和其他长链碱基在内的许多鞘脂代谢产物可以有效诱导人类肝癌细胞的细胞凋亡。在这项研究中，我们研究了鞘氨醇可能通过抑制抗凋亡途径引发人肝癌细胞凋亡的可能性。我们研究了鞘氨醇对AKT激酶的影响，AKT激酶是一种丝氨酸/苏氨酸激酶，被发现可以保护细胞免受各种细胞外应激诱导的凋亡。我们的研究结果表明，鞘氨醇抑制基础和血清刺激的AKT激酶活性在肝癌细胞中以剂量依赖的方式。此外，鞘氨醇诱导的AKT激酶抑制与这些细胞中的凋亡诱导相关。胰岛素是AKT激酶的一种强有力的刺激剂，胰岛素的预处理部分逆转了鞘氨醇对AKT激酶的抑制，并抵消了这种鞘脂的凋亡作用。活化的AKT激酶的表达部分保护细胞免受鞘氨醇诱导的凋亡，而激酶死亡的AKT激酶的表达没有影响。研究AKT激酶抑制鞘氨醇凋亡作用的分子机制。我们的研究结果表明，增加释放细胞色素C从线粒体和随后的激活caspase-3的鞘氨醇处理的肝癌细胞检测。相反，在Hep 3B细胞中激活的AKT激酶的表达减弱了鞘氨醇诱导的细胞色素C释放和caspase-3激活。总之，这些研究结果表明，AKT激酶的抑制是鞘氨醇诱导肝癌细胞凋亡的机制之一，AKT激酶的激活可能通过阻断细胞色素C释放和caspase-3激活的上游步骤来抑制鞘氨醇诱导的细胞凋亡。(C)2001 Wiley-Liss，Inc.
Our previous work has shown that a number of sphingolipid metabolites including sphingosine, sphinganine, and other long-chain bases potently induced apoptosis in human hepatoma cells. in this study, we examined the possibility that sphingosine may trigger apoptosis in human hepatoma cells via inhibition of anti-apoptotic pathways. We investigated the effect of sphingosine on AKT kinase, a serine/threonine kinase which was found to protect cells from apoptosis induced by a variety of extracellular stresses. Our results indicated that sphingosine inhibited basal and serum-stimulated AKT kinase activity in a dose-dependent manner in hepatoma cells. Additionally, sphingosine-induced inhibition of AKT kinase was correlated with induction of apoptosis in these cells. Pretreatment of insulin, a potent stimulator of AKT kinase, partially reversed the inhibition of AKT kinase by sphingosine and counteracted the apoptotic action of this sphingolipid. Expression of activated AKT kinase partially protected cells from sphingosine-induced apoptosis, whereas expression of kinase-dead AKT kinase had no effect. The molecular mechanism by which AKT kinase suppressed the apoptotic action of sphingosine was investigated. Our results showed that increased release of cytochrome C from mitochondria and subsequent activation of caspase-3 were detected in sphingosine-treated hepatoma cells. On the contrary, expression of activated AKT kinase in Hep3B cells attenuated cytochrome C release and caspase-3 activation induced by sphingosine. Taken together, these findings suggest that suppression of AKT kinase is one of the mechanisms by which sphingosine induces apoptosis in hepatoma cells and activation of AKT kinase may inhibit sphingosine-induced apoptosis by blocking a step upstream of cytochrome C release and caspase-3 activation. (C) 2001 Wiley-Liss, Inc.