p28GANK knockdown-derived reactive oxygen species induces apoptosis through mitochondrial dysfunction mediated by p38 in HepG2 cells.
p28GANK knockdown-derived reactive oxygen species induces apoptosis through mitochondrial dysfunction mediated by p38 in HepG2 cells.
复制标题
p28GANK 敲低衍生的活性氧通过 p38 介导的 HepG2 细胞线粒体功能障碍诱导细胞凋亡。
DOI：
10.3892/ijo_00000060
复制
发表时间：
2008
影响因子：
5.2
通讯作者：
Hongyang Wang
中科院分区：
文献类型：
--
作者：
Xue;Honghai Li;Yao Chen;Jing Fu;Y. Ren;Liwei Dong;Shanhua Tang;Shu;Meng;Hongyang Wang
RNA干扰(RNAi)下调癌蛋白p28GANK可诱导肝癌细胞凋亡。然而，这些机制还没有得到很好的定义。在本研究中，caspase-9抑制剂(Z-Lehd-FMK)可阻止p28GANK基因敲除诱导的HepG2细胞凋亡。在p28GANK基因敲除过程中，观察到线粒体Bax易位、线粒体跨膜电位丧失(DeltaPsim)和细胞色素c的释放。在本研究中，p38的激活在p28GANK基因敲除诱导的细胞凋亡中起关键作用，这一发现表明，SB203580对p38的药理抑制抑制了Bax的重新分布，DeltaPsim的丢失和细胞凋亡。此外，活性氧(ROS)清除剂N-乙酰-L半胱氨酸(NAC)抑制了p38的磷酸化，抑制了细胞的凋亡，因此ROS的产生有助于细胞死亡。我们的研究建立了p28GANK基因敲除诱导HepG2细胞凋亡的信号通路，即细胞内ROS生成下游p38介导的线粒体功能障碍。
Oncoprotein p28GANK knockdown by RNA interference (RNAi) can induce hepatoma cells apoptosis. However, the mechanisms have not been well defined yet. In the present study the p28GANK knockdown-induced apoptosis in HepG2 cells was prevented by caspase-9 inhibitor (Z-LEHD-FMK). During the knockdown of p28GANK, mitochondrial translocation of Bax, loss of mitochondrial transmembrane potential (DeltaPsim) and release of cytochrome c were observed. In this study, the activation of p38 was found to be critical for the p28GANK knockdown-induced apoptosis, as suggested by the finding that pharmacological inhibition of p38 with SB203580 suppressed the redistribution of Bax, the loss of DeltaPsim and the apoptosis. Moreover, generation of reactive oxygen species (ROS) contributed to the cell death because N-acetyl-L-cystenine (NAC), a ROS scavenger, suppressed the phosphorylation of p38 and the apoptosis. Our studies established the signaling pathway of p28GANK knockdown-induced apoptosis in HepG2 cells, namely, mitochondrial dysfunction mediated by p38 downstream of intracellular ROS generation.