MAPK signaling pathways regulate mitochondrial-mediated apoptosis induced by isoorientin in human hepatoblastoma cancer cells.
MAPK signaling pathways regulate mitochondrial-mediated apoptosis induced by isoorientin in human hepatoblastoma cancer cells.
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DOI：
10.1016/j.fct.2012.11.048
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发表时间：
2013-03
期刊：
影响因子：
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通讯作者：
Linli Yuan;Jing Wang;Haifang Xiao;Wanqiang Wu;Yutang Wang;Xuebo Liu
中科院分区：
文献类型：
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作者：
Linli Yuan;Jing Wang;Haifang Xiao;Wanqiang Wu;Yutang Wang;Xuebo Liu
异orientin（ISO）（CAS RN：4261-42-1）是一种黄酮类化合物，可以从几种植物中提取，如毛竹、败酱和Drosophyllum lusitanicum。ISO可通过线粒体功能障碍和抑制PI 3 K/Akt信号通路诱导HepG 2细胞凋亡，但其对MAPK信号通路的影响尚不清楚。本研究探讨了ISO对这一通路的影响，以及MAPK激酶在细胞凋亡中的作用。结果表明，ISO诱导HepG 2细胞死亡具有剂量和时间依赖性，诱导细胞凋亡是ISO诱导HepG 2细胞毒性的主要原因。ISO可显著抑制ERK 1/2激酶的表达，增加JNK和p38激酶的表达。此外，U 0126（ERK 1/2抑制剂）显着增强ISO诱导的Bax/Bcl-2的比例，细胞色素c的释放到胞质溶胶部分，和切割的caspase-3的水平。而JNK抑制剂SP 600125和p38抑制剂SB 203580则能明显抑制ISO诱导的这些蛋白的表达。ROS抑制剂NAC可显著增强ISO对ERK 1/2激酶的抑制作用。NAC还抑制p-JNK和p-p38，但不能逆转ISO的作用。这些结果首次证明了ISO通过灭活ERK 1/2激酶和激活JNK和p38激酶诱导HepG 2细胞凋亡，并且ISO刺激的ROS能够作为上游信号分子激活MAPK信号通路。ISO介导的细胞凋亡的起始事件是MAPK信号。
Isoorientin (ISO) (CAS RN: 4261-42-1) is a flavonoid compound that can be extracted from several plant species, such as Phyllostachys pubescens, Patrinia, and Drosophyllum lusitanicum. ISO is able to induce apoptosis through mitochondrial dysfunction and inhibition of PI3K/Akt signaling pathway in HepG2 cells, however, the effects of ISO on MAPK signaling pathways remain unknown. The present study investigated the effects of ISO on this pathway, and the roles of MAPK kinases on mitochondrial-mediated apoptosis in HepG2 cells. The results showed that ISO induced cell death in a dose- and time-dependent manner, and induction apoptosis is main cause for ISO-induced cytotoxicity in HepG2 cells. ISO significantly inhibited the levels of ERK1/2 kinase and increased the expression of JNK and p38 kinases. Furthermore, U0126 (an ERK1/2 inhibitor) significantly enhanced the ISO-induced the Bax/Bcl-2 ratio, the release of cytochrome c to the cytosol fraction, and the levels of cleaved caspase-3. While SP600125 (a JNK inhibitor) and SB203580 (a p38 inhibitor) markedly prevented the expression of these proteins induced by ISO. Furthermore, the ROS inhibitor (NAC) notably promoted the inhibited effect of ISO on the ERK1/2 kinase. NAC also suppressed the p-JNK and p-p38, but failed to reverse the effects of ISO. These results demonstrated for the first time that ISO induces apoptosis in HepG2 cells through inactivating ERK1/2 kinase and activating JNK and p38 kinases, and ROS stimulated by ISO is able to activate the MAPK singaling pathway as the upstream signaling molecules. Initiating event of the mitochondrial-mediated apoptosis induced by ISO is MAPK signals.