6-Shogaol induces apoptosis in human hepatocellular carcinoma cells and exhibits anti-tumor activity in vivo through endoplasmic reticulum stress.
6-Shogaol induces apoptosis in human hepatocellular carcinoma cells and exhibits anti-tumor activity in vivo through endoplasmic reticulum stress.
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6-Shogaol 诱导人肝细胞癌细胞凋亡，并通过内质网应激在体内表现出抗肿瘤活性。
DOI：
10.1371/journal.pone.0039664
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Li P
中科院分区：
文献类型：
--
作者：
Hu R;Zhou P;Peng YB;Xu X;Ma J;Liu Q;Zhang L;Wen XD;Qi LW;Gao N;Li P
6-姜烯酚是从生姜中分离出的一种活性化合物。在这项工作中，我们证明了6-姜烯酚诱导人肝癌细胞凋亡与caspase激活和内质网（ER）应激信号有关。蛋白质组学分析表明，ER应激伴随着6-姜烯酚诱导的肝癌细胞凋亡。6-姜烯酚通过调节未折叠蛋白反应（UPR）传感器PERK及其下游靶点eIF 2 α影响内质网应激信号转导。而对另外两个UPR传感器IRE 1和ATF 6的影响不明显。在长时间内质网应激中，6-姜烯酚可抑制SMMC-7721细胞eIF 2 α的磷酸化并引发细胞凋亡。Salubrinal是PERK/eIF 2 α通路的激活剂，显著增强SMMC-7721细胞中eIF 2 α的磷酸化，而没有毒性。而6-姜烯酚和salubrinal联合处理则导致细胞凋亡和eIF 2 α的去磷酸化。在SMMC-7721细胞中，eIF 2 α过表达可抑制6-姜烯酚介导的细胞凋亡，而小干扰RNA抑制eIF 2 α可显著增强6-姜烯酚介导的细胞死亡。此外，6-姜烯酚介导的对小鼠SMMC-7721异种移植瘤生长的抑制与诱导细胞凋亡、激活caspase-3和灭活eIF 2 α相关。总之，我们的研究结果表明，PERK/eIF 2 α通路在6-姜烯酚介导的SMMC-7721细胞的ER应激和凋亡中起着重要作用。
6-Shogaol is an active compound isolated from Ginger (Zingiber officinale Rosc). In this work, we demonstrated that 6-shogaol induces apoptosis in human hepatocellular carcinoma cells in relation to caspase activation and endoplasmic reticulum (ER) stress signaling. Proteomic analysis revealed that ER stress was accompanied by 6-shogaol-induced apoptosis in hepatocellular carcinoma cells. 6-shogaol affected the ER stress signaling by regulating unfolded protein response (UPR) sensor PERK and its downstream target eIF2α. However, the effect on the other two UPR sensors IRE1 and ATF6 was not obvious. In prolonged ER stress, 6-shogaol inhibited the phosphorylation of eIF2α and triggered apoptosis in SMMC-7721 cells. Salubrinal, an activator of the PERK/eIF2α pathway, strikingly enhanced the phosphorylation of eIF2α in SMMC-7721 cells with no toxicity. However, combined treatment with 6-shogaol and salubrinal resulted in significantly increase of apoptosis and dephosphorylation of eIF2α. Overexpression of eIF2α prevented 6-shogaol-mediated apoptosis in SMMC-7721 cells, whereas inhibition of eIF2α by small interfering RNA markedly enhanced 6-shogaol-mediated cell death. Furthermore, 6-shogaol-mediated inhibition of tumor growth of mouse SMMC-7721 xenograft was associated with induction of apoptosis, activation of caspase-3, and inactivation of eIF2α. Altogether our results indicate that the PERK/eIF2α pathway plays an important role in 6-shogaol-mediated ER stress and apoptosis in SMMC-7721 cells in vitro and in vivo.
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DOI：
10.1016/j.bbrc.2007.08.012
发表时间：
2007-10-12
影响因子：
3.1
作者：
Ishiguro, Kazuhiro;Ando, Takafumi;Goto, Hidemi
通讯作者：
Goto, Hidemi
影响因子：
25.7
作者：
Malhi, Harmeet;Kaufman, Randal J.
通讯作者：
Kaufman, Randal J.
影响因子：
8
作者：
Gao, N;Rahmani, M;Grant, S
通讯作者：
Grant, S
影响因子：
4.8
作者：
Cnop, Miriam;Ladriere, Laurence;Eizirik, Decio L.
通讯作者：
Eizirik, Decio L.
影响因子：
6.1
作者：
Chen, Chung-Yi;Liu, Tsan-Zon;Chen, Ching-Hsein
通讯作者：
Chen, Ching-Hsein