Paris saponin VII inhibits growth of colorectal cancer cells through Ras signaling pathway
Paris saponin VII inhibits growth of colorectal cancer cells through Ras signaling pathway
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重楼皂苷VII通过Ras信号通路抑制结直肠癌细胞生长
DOI：
10.1016/j.bcp.2014.01.018
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发表时间：
2014-03-15
影响因子：
5.8
通讯作者：
Mei, Qibing
中科院分区：
文献类型：
--
作者：
Li, Yuhua;Sun, Yang;Mei, Qibing
Ras信号通路的失调在结直肠癌的进展中起着关键作用。当与GTP结合时，Ras被激活并刺激几种下游效应物的途径，包括Raf/MEK/ERK激酶级联、PI 3-激酶/AKT/mTor途径和Ral GT3途径。从百合科草本植物中提取的皂甙具有较强的抗肿瘤活性，且毒性较低。在这项研究中，巴黎皂苷VII（PSVII），分离自延龄草，在人结肠直肠癌细胞（HT-29和SW-620）、结肠炎相关结肠直肠癌（CACC）的小鼠模型和异种移植肿瘤的鼠模型上评估。发现PSVII以浓度依赖性方式抑制结肠直肠癌细胞生长。PSVII对HT-29和SW-620细胞生长抑制的IC 50值分别为1.02 +/- 0.05 μ M和4.90 +/- 0.23 μ M。它可以诱导细胞凋亡，细胞周期阻滞在G（1）期，并以caspase-3依赖的方式触发凋亡。PSVII诱导的生长抑制作用与通过下调MEK 1/2、ERK 1/2磷酸化而干扰MAPK通路以及通过降低AKT和GSK-3 β磷酸化而抑制AKT通路有关。在CACC小鼠模型中，PSVII保护小鼠免受1，2-二甲基肼（DMH）和葡聚糖硫酸钠（DSS）诱导的肠道毒性和致癌作用。在异种移植瘤模型中，PSVII显著减小了异种移植瘤的大小，并引发了肿瘤细胞的凋亡。体外和体内研究均表明PSVII抑制Ras活性。因此，PSVII有望成为一种靶向Ras信号通路的大肠癌治疗药物。(C)2014爱思唯尔公司All rights reserved.
Dysregulation of the Ras signaling pathway plays a key role in the progression of colorectal cancer. When bound to GTP, Ras is activated and stimulates several downstream effectors' pathways, including the Raf/MEK/ERK kinase cascade, the PI3-kinase/AKT/mTor pathway, and the Ral GTPase pathway. Saponins extracted from Liliaceae family herbs have strong antitumor activities with low toxicity. In this study, Paris saponin VII (PSVII), isolated from Trillium tschonoskii Maxim., was evaluated on human colorectal cancer cells (HT-29 and SW-620), a mouse model of colitis associated colorectal cancer (CACC) and a murine model of xenograft tumor. It was found that PSVII inhibited colorectal cancer cell growth in a concentration-dependent manner. The IC50 values of PSVII for growth inhibition of HT-29 and SW-620 cells were 1.02 +/- 0.05 mu M and 4.90 +/- 0.23 mu M. It could induce cell apoptosis, together with cell cycle arrest in G(1) phase, and trigger apoptosis in a caspase-3-dependent manner. PSVII-induced growth inhibitory effect was associated with disturbance of MAPK pathway by down-regulating MEK1/2, ERK1/2 phosphorylation, and suppression of AKT pathway by reducing AKT and GSK-3 beta phosphorylation. In the CACC mouse model, PSVII protected mice from intestinal toxicities and carcinogenesis induced by 1,2-dimethylhydrazine (DMH) and dextran sodium sulfate (DSS). In the model of xenograft tumor, PSVII remarkably decreased the xenograft tumor size and triggered the apoptosis of tumor cells. Both in vitro and in vivo study showed that PSVII inhibited Ras activity. Taken together, PSVII might be a potential therapeutic reagent for colorectal cancer through targeting Ras signaling pathway. (C) 2014 Elsevier Inc. All rights reserved.