[1]王 雪,毕宇宁,闫文帝,等.AZD8055抑制胆管癌细胞HuCCT1的迁移及EMT进程的机制研究[J].中国药理学通报,2019,(10):1429-1436.[doi:10.3969/j.issn.1001-1978.2019.10.018]
 WANG Xue,BI Yu-ning,YAN Wen-di,et al.Study on mechanism of AZD8055 inhibiting migration and EMT progression of cholangiocarcinoma cell HuCCT1[J].Chinese Pharmacological Bulletin,2019,(10):1429-1436.[doi:10.3969/j.issn.1001-1978.2019.10.018]
点击复制

AZD8055抑制胆管癌细胞HuCCT1的迁移及EMT进程的机制研究()
分享到:

《中国药理学通报》[ISSN:/CN:]

卷:
期数:
2019年10期
页码:
1429-1436
栏目:
论著
出版日期:
2019-09-15

文章信息/Info

Title:
Study on mechanism of AZD8055 inhibiting migration and EMT progression of cholangiocarcinoma cell HuCCT1
文章编号:
1001-1978(2019)10-1429-08
作者:
王 雪13毕宇宁13闫文帝13张 鑫13董 颖13匡子藤13林贞花123任香善123
延边大学1.肿瘤研究中心、2.医学院病理学教研室、3.吉林省科技厅重点实验室,吉林 延吉 133002
Author(s):
WANG Xue13 BI Yu-ning1 3 YAN Wen-di13 ZHANG Xin13 DONG Ying1 3 KUANG Zi-teng1 3 LIN Zhen-hua123 REN Xiang-shan123
1.Cancer Research Center, Yanbian University; 2.Dept of Pathology, Yanbian University Medical College; 3.Key Lab of the Science and Technology Dept of Jilin Province, Yanji Jiling 133002, China
关键词:
AZD8055 胆管癌 DEK 上皮-间质转化 增殖 迁移 Akt/mTOR信号通路
Keywords:
AZD8055 cholangiocarcinoma DEK EMT proliferation migration Akt/mTOR signaling pathway
分类号:
R329.24; R394.2; R735.8; R916.4; R977.6
DOI:
10.3969/j.issn.1001-1978.2019.10.018
文献标志码:
A
摘要:
目的 探讨哺乳动物雷帕霉素靶蛋白(mTOR)双重抑制剂AZD8055在抑制人胆管癌细胞HuCCT1的迁移及EMT进程中的作用及分子机制。方法 MTT法与平板克隆形成实验检测AZD8055对胆管癌细胞增殖的影响; 划痕愈合实验和Transwell小室迁移实验检测AZD8055对HuCCT1细胞迁移能力的影响; Western blot法检测EMT标志相关蛋白、Akt/mTOR信号通路蛋白及DEK蛋白的表达; 利用STITCH、GeneMANIA数据库,分析AZD8055、DEK、Akt信号通路相互作用关系; 在DEK基因沉默后,检测胆管癌细胞增殖活力、迁移能力及Akt/mTOR信号通路相关蛋白表达水平的变化。结果 AZD8055可抑制胆管癌细胞的增殖及迁移能力,同时抑制Akt/mTOR信号通路相关蛋白、DEK蛋白表达及EMT的进程; 沉默DEK基因可明显抑制胆管癌细胞增殖及迁移能力,并降低Akt、S6、4EBP1蛋白的磷酸化水平。结论 AZD8055抑制HuCCT1细胞的迁移及EMT进程,其机制与下调DEK,抑制Akt/mTOR信号通路有关。
Abstract:
Aim To investigate the molecular mechanisms of the dual inhibitor of mammalian rapamycin target protein(mTOR)AZD8055 in migration and EMT process inhibition of the human cholangiocarcinoma cell line HuCCT1.Methods The viability of HuCCT1 cells treated with different concentrations of AZD8055 was measured by MTT assay, and the colony formation ability of HuCCT1 was detected by colony formation assay.The effect of AZD8055 on the motility of HuCCT1 cells was examined by wound healing assay and Transwell assay.The expression levels of the protein associated with Akt/mTOR pathway, epithelial-mesenchymal transition(EMT)process and DEK were detected by Western blot.The interaction relationship between AZD8055, DEK and Akt signaling pathway was analyzed by STITCH and GeneMania databases.Cholangiocarcinoma cells'proliferation, migration capacities and Akt/mTOR signaling pathway-related protein expression levels were detected after DEK gene silencing.Results Compared with control group, AZD8055 inhibited the proliferation and migration capacities of cholangiocarcinoma cells, and suppressed the expression levels of Akt/mTOR signaling pathway-related markers, down-regulated DEK expression and inhibited EMT process.DEK silence significantly inhibited cell proliferation, migration and significantly decreased the phosphorylation levels of Akt, S6, and 4EBP1.Conclusions AZD8055 treatment inhibits the migration and EMT progression of HuCCT1 cells, and its mechanism is associated with DEK down-regulation and inhibition of Akt/mTOR signaling pathway.

参考文献/References:

[1] Valle J W, Lamarca A,Goyal L.New horizons for precision medicine in biliary tract cancers[J].Cancer Discov, 2017, 7(9): 943-62.
[2] Doherty B, Nambudiri V E, Palmer W C.Update on the diagnosis and treatment of cholangiocarcinoma[J].Curr Gastroenterol Rep, 2017, 7(19):2.
[3] 朱泽斌, 叶林森, 郑朝旭.PI3K/Akt信号通路在胆管癌中的作用[J].中华肝脏外科手术学电子杂志, 2016, 5(5):330.
[3] Zhu Z B, Ye L S, Zheng Z X.Role of PI3K/Akt signaling pathway in cholangiocarcinoma[J].Chin J Hepatol Surgery, 2016, 5(5):330.
[4] Pétigny-Lechartier C, Duboc C, Jebahi A, et al.The mTORC1/2 inhibitor AZD8055 strengthens the efficiency of the MEK inhibitor trametinib to reduce the Mcl-1/[Bim and Puma] ratio and to sensitize ovarian carcinoma cells to ABT-737[J].Mol Cancer Ther, 2017, 16(1):102-15.
[5] 陈柯君.雷帕霉素耐药机制及其逆转途径[J].国际肿瘤学杂志, 2014, 41(10):740-3.
[5] Chen K J.Mechanism of rapamycin resistance and its reversal pathway[J].Int J Oncol, 2014, 41(10): 740-3.
[6] 张铮铮, 刘 筱, 徐 浩, 等.骨化三醇、雷帕霉素及其联合使用对人子宫内膜癌Ishikawa细胞株的作用及机制研究[J].中国药理学通报, 2018, 34(10): 1444-9.
[6] Zhang Z Z, Liu X, Xu H, et al.Effect of calcitriol, rapamycin and their combination on human endometrial carcinoma Ishikawa cells in vitro and its mechanism[J].Chin Pharmacol Bull, 2018, 34(10): 1444-9.
[7] 李 鹏, 王亚红, 杨拉维, 等.AZD8055 抑制肝癌huh7细胞增殖和促细胞凋亡[J].基础医学与临床, 2014, 4(6): 771-5.
[7] Li P, Wang Y H, Yang L W, et al.AZD8055 inhibits proliferation and promotes apoptosis of liver cancer huh7 cells[J].Basic Med Clin, 2014, 4(6): 771-5.
[8] Xu D Q, Toyoda H, Qi L, et al.Induction of MEK/ERK activity by AZD8055 confers acquired resistance in neuroblastoma[J].Biochem Biophys Res Commun, 2018, 499(3):425-32.
[9] 刘特思.虫草素靶向DEK调控Akt及Erk1/2信号通路抑制胆管癌增殖和迁移的机制研究[D].延边大学, 2018.
[9] Liu T S.Mechanism of Cordycepin targeting DEK to regulate Akt and Erk1/2 signaling pathways inhibiting proliferation and migration of cholangiocarcinoma[D].Yanbian University, 2018.
[10] Xu X, Zou L, Yao Q, et al.Silencing DEK downregulates cervical cancer tumorigenesis and metastasis via the DEK/p-Ser9-GSK-3β/p-Tyr216-GSK-3β/β-catenin axis[J].Oncol Rep, 2017, 38(2):1035-42.
[11] Wu X, Wu G, Wu Z, et al.MiR-200a suppresses the proliferation and metastasis in pancreatic ductal adenocarcinoma through downregulation of DEK gene[J].Transl Onco, 2016, 9(1):25-31.
[12] Willems L, Chapuis N, Puissant A, et al.The dual mTORC1 and mTORC2 inhibitor AZD8055 has anti-tumor activity in acute myeloid leukemia[J].Leukemia, 2011, 26(6):1195-202.
[13] Giubellino A, Bullova P, Nölting S, et al.Combined inhibition of mTORC1 and mTORC2 signaling pathways is a promising therapeutic option in inhibiting pheochromocytoma tumor growth: in vitro and in vivo studies in female athymic nude mice[J].Endocrinology, 2013, 154(2):646-55.
[14] Chen J, Zhao K N, Li R, et al.Activation of PI3K/Akt/mTOR pathway and dual inhibitors of PI3K and mTOR in endometrial cancer[J].Curr Med Chem, 2014, 21: 3070-80.
[15] Nörz D, Grottke A, Bach J, et al.Discontinuing MEK inhibitors in tumor cells with an acquired resistance increases migration and invasion[J].Cell Signal, 2015, 27(11):2191-200.
[16] Yang Y, Gao M, Lin Z, et al.DEK promoted EMT and angiogenesis through regulating PI3K/AKT/mTOR pathway in triple-negative breast cancer[J].Oncotarget, 2017, 8(58):98708-22.

备注/Memo

备注/Memo:
收稿日期:2019-05-15,修回日期:2019-06-21 基金项目:国家自然科学基金资助项目(No 31460303,81660609); 吉林省科技厅自然科学基金项目(No 20180101007); 吉林省教育厅自然科学基金项目(No JJKH20191116KJ) 作者简介:王 雪(1991-),女,硕士生,研究方向:肿瘤分子病理学,E-mail:825811349@qq.com; 任香善(1976-),女,博士,副教授,硕士生导师,研究方向:肿瘤分子病理学,通讯作者,Tel:0433-2435092,E-mail: renxsh@ybu.edu.cn
更新日期/Last Update: 2019-09-15