隐丹参酮通过JAK2/STAT3和PI3K/Akt/NFκB信号通路诱导胆管癌细胞的细胞周期阻滞和凋亡。
Cryptotanshinone induces cell cycle arrest and apoptosis through the JAK2/STAT3 and PI3K/Akt/NFκB pathways in cholangiocarcinoma cells.
作者信息
Ke Fayong, Wang Zheng, Song Xiaoling, Ma Qiang, Hu Yunping, Jiang Lin, Zhang Yijian, Liu Yingbin, Zhang Yong, Gong Wei
机构信息
Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
Institute of Biliary Disease Research, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
出版信息
Drug Des Devel Ther. 2017 Jun 15;11:1753-1766. doi: 10.2147/DDDT.S132488. eCollection 2017.
BACKGROUND
Cholangiocarcinoma (CCA) is the most common biliary tract malignancy in the world with high resistance to current chemotherapies and extremely poor prognosis. The main objective of this study was to investigate the inhibitory effects of cryptotanshinone (CTS), a natural compound isolated from , on CCA both in vitro and in vivo and to explore the underlying mechanisms of CTS-induced apoptosis and cell cycle arrest.
METHODS
The anti-tumor activity of CTS on HCCC-9810 and RBE cells was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay and colony forming assays. Cell cycle changes were detected by flow cytometric analysis. Apoptosis was detected by annexin V/propidium iodide double staining and Hoechst 33342 staining assays. The efficacy of CTS in vivo was evaluated using a HCCC-9810 xenograft model in athymic nude mice. The expression of key proteins involved in cell apoptosis and signaling pathway in vitro was analyzed by Western blot analysis.
RESULTS
CTS induced potent growth inhibition, S-phase arrest, apoptosis, and colony-forming inhibition in HCCC-9810 and RBE cells in a dose-dependent manner. Intraperitoneal injection of CTS (0, 10, or 25 mg/kg) for 4 weeks significantly inhibited the growth of HCCC-9810 xenografts in athymic nude mice. CTS treatment induced S-phase arrest with a decrease of cyclin A1 and an increase of cyclin D1 protein level. Bcl-2 expression was downregulated remarkably, while Bax expression was increased after apoptosis occurred. Additionally, the activation of JAK2/STAT3 and PI3K/Akt/NFκB was significantly inhibited in CTS-treated CCA cells.
CONCLUSION
CTS induced CCA cell apoptosis by suppressing both the JAK2/STAT3 and PI3K/Akt/NFκB signaling pathways and altering the expression of Bcl-2/Bax family, which was regulated by these two signaling pathways. CTS may serve as a potential therapeutic agent for CCA.
背景
胆管癌（CCA）是全球最常见的胆道恶性肿瘤，对当前化疗具有高度抗性，预后极差。本研究的主要目的是研究隐丹参酮（CTS）（一种从[具体来源未给出]分离出的天然化合物）在体外和体内对CCA的抑制作用，并探讨CTS诱导细胞凋亡和细胞周期阻滞的潜在机制。
方法
通过3-(4,5-二甲基噻唑-2-基)-2,5-二苯基溴化四氮唑（MTT）法和集落形成试验评估CTS对HCCC-9810和RBE细胞的抗肿瘤活性。通过流式细胞术分析检测细胞周期变化。通过膜联蛋白V/碘化丙啶双染法和Hoechst 33342染色试验检测细胞凋亡。使用无胸腺裸鼠中的HCCC-9810异种移植模型评估CTS在体内的疗效。通过蛋白质免疫印迹分析体外分析参与细胞凋亡和信号通路的关键蛋白的表达。
结果
CTS以剂量依赖性方式诱导HCCC-9810和RBE细胞产生强大的生长抑制、S期阻滞、细胞凋亡和集落形成抑制。腹腔注射CTS（0、10或25mg/kg）4周可显著抑制无胸腺裸鼠中HCCC-9810异种移植瘤的生长。CTS处理诱导S期阻滞，同时细胞周期蛋白A1水平降低，细胞周期蛋白D1蛋白水平升高。凋亡发生后，Bcl-2表达显著下调，而Bax表达增加。此外，在CTS处理的CCA细胞中，JAK2/STAT3和PI3K/Akt/NFκB的激活受到显著抑制。
结论
CTS通过抑制JAK2/STAT3和PI3K/Akt/NFκB信号通路以及改变受这两条信号通路调控的Bcl-2/Bax家族的表达来诱导CCA细胞凋亡。CTS可能作为CCA的一种潜在治疗药物。
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