Cryptotanshinone induces cell cycle arrest and apoptosis through the JAK2/STAT3 and PI3K/Akt/NFκB pathways in cholangiocarcinoma cells.
Cryptotanshinone induces cell cycle arrest and apoptosis through the JAK2/STAT3 and PI3K/Akt/NFκB pathways in cholangiocarcinoma cells.
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隐丹参酮通过 JAK2/STAT3 和 PI3K/Akt/NF kappa B 通路诱导胆管癌细胞的细胞周期停滞和细胞凋亡
DOI：
10.2147/dddt.s132488
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Gong W
中科院分区：
文献类型：
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作者：
Ke F;Wang Z;Song X;Ma Q;Hu Y;Jiang L;Zhang Y;Liu Y;Zhang Y;Gong W
胆管细胞癌(CCA)是世界上最常见的胆道恶性肿瘤，对目前的化疗方案耐受性高，预后极差。本研究的主要目的是研究丹参天然成分隐丹参酮(CTS)在体内外对CCA的抑制作用，探讨CTS诱导细胞凋亡和细胞周期停滞的可能机制。采用四甲基偶氮唑蓝(3-(4，5-dimethylthiazol-2-yl)-2，5-diphenyl-tetrazolium)比色法和集落形成实验检测CTS对人肝癌细胞株HCC9810和RBE细胞的抑瘤活性。流式细胞仪检测细胞周期变化。Annexin V/碘化丙啶双重染色和Hoechst 33342染色检测细胞凋亡。采用裸鼠HCCC-9810异种移植模型评价CTS的体内疗效。Western印迹分析细胞凋亡及信号转导途径中关键蛋白的表达。CTS以剂量依赖方式诱导HCCC9810和RBE细胞生长抑制、S期阻滞、细胞凋亡和集落形成抑制。连续4周腹腔注射CTS(0、10、25 mg/kg)可显著抑制裸鼠移植瘤的生长。三七总皂甙处理后，细胞周期蛋白A1减少，细胞周期蛋白D1蛋白水平升高，使细胞周期停滞于S时相。细胞发生凋亡后，bcl2表达明显下调，而bax表达增加。此外，CTS还可显著抑制κB的激活。CTS通过抑制JAK2/STAT3和PI3K/AKT/NFBcl2/κB信号通路，改变受这两条信号通路调控的Bcl2/Bax家族的表达，从而诱导血管内皮细胞凋亡。CTS有可能成为治疗CCA的潜在药物。
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 Salvia miltiorrhiza Bunge, on CCA both in vitro and in vivo and to explore the underlying mechanisms of CTS-induced apoptosis and cell cycle arrest. 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. 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. 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.