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学科主题临床医学
PP242 suppresses cell proliferation, metastasis, and angiogenesis of gastric cancer through inhibition of the PI3K/AKT/mTOR pathway
Xing, Xiaofang1; Zhang, Lianhai2; Wen, Xianzi1; Wang, Xiaohong3; Cheng, Xiaojing1; Du, Hong1; Hu, Ying3; Li, Lin1; Dong, Bin4; Li, Ziyu2; Ji, Jiafu1,2,3
关键词Angiogenesis Gastric Cancer Metastasis Mammalian Target Of Rapamycin Inhibitor Proliferation
刊名ANTI-CANCER DRUGS
2014-11-01
DOI10.1097/CAD.0000000000000148
25期:10页:1129-1140
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Oncology ; Pharmacology & Pharmacy
研究领域[WOS]Oncology ; Pharmacology & Pharmacy
关键词[WOS]MTOR KINASE INHIBITOR ; SIGNALING PATHWAY ; TARGETING MTOR ; RAPAMYCIN ; THERAPY ; EXPRESSION ; DRUG
英文摘要

Although preclinical work with rapalogs suggests potential in the treatment of gastric cancer, they have been less successful clinically. In this study, we report the impact of the investigational drug PP242, a potent and selective small-molecule active-site TORC1/2 kinase inhibitor, on tumor growth and metastasis. The antiproliferative effect of PP242 was assessed using the Cell Counting Kit-8 assay. The migration and invasion potential were analyzed using wound-healing and transwell assays, respectively. The Matrigel capillary tube formation assay was performed to mimic in-vivo angiogenesis. Immunoblotting and immunofluorescence were used to observe protein levels and distribution of actin fibers. Finally, S2448p-mammalian target of rapamycin (mTOR) expression was detected on gastric cancer tissues using immunohistochemistry. First, PP242 potently inhibited cell proliferation in gastric cancer cell lines and in human endothelial cells in vitro at the IC50 ranged from 50 to 500 nmol/l. Then, an inhibitory effect of PP242 on metastasis was observed in gastric cancer cell AGS, along with the cytoskeletal rearrangements and suppression of the phosphorylation of PI3K downstream factors including AKT, mTOR, and P70S6K. Furthermore, PP242 was found to decrease the tube formation and migration of human umbilical vein endothelial cells. Using immunohistochemistry, we found that S2448p-mTOR staining was observed in 41.8% (82/196) of gastric cancer tissues and correlated with depth of mural invasion, lymph node metastasis, tumor node metastasis stage, and vascular invasion. These results show that PP242 suppresses cell proliferation and angiogenesis of gastric cancer through inhibition of the PI3K/AKT/mTOR pathway, which might be an effective novel therapeutic candidate against gastric cancer in the future. (C) 2014 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

语种英语
WOS记录号WOS:000343234900003
项目编号320.6700.09009 ; 20110001120067 ; 81101881 ; 81341072 ; 2014AA020603
资助机构WuJieping cancer target therapy research foundation ; Specialized Research Fund for the doctoral Program of Higher Education ; National Nature Science Foundation of China ; National High Technology Research and Development Program of China (863 Program)
引用统计
被引频次:19[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/50997
专题北京大学临床肿瘤学院_胃肠肿瘤中心
北京大学临床肿瘤学院_胃肠肿瘤中心一病区
北京大学临床肿瘤学院_中心实验室
北京大学临床肿瘤学院_标本库
作者单位1.Peking Univ, Beijing Canc Hosp & Inst, Dept Gastrointestinal Translat Res, Key Lab Carcinogenesis & Translat Res,Minist Educ, Beijing 100142, Peoples R China
2.Peking Univ, Beijing Canc Hosp & Inst, Dept Gastrointestinal Surg, Key Lab Carcinogenesis & Translat Res,Minist Educ, Beijing 100142, Peoples R China
3.Peking Univ, Beijing Canc Hosp & Inst, Dept Tissue Bank, Key Lab Carcinogenesis & Translat Res,Minist Educ, Beijing 100142, Peoples R China
4.Peking Univ, Beijing Canc Hosp & Inst, Dept Pathol, Key Lab Carcinogenesis & Translat Res,Minist Educ, Beijing 100142, Peoples R China
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GB/T 7714
Xing, Xiaofang,Zhang, Lianhai,Wen, Xianzi,et al. PP242 suppresses cell proliferation, metastasis, and angiogenesis of gastric cancer through inhibition of the PI3K/AKT/mTOR pathway[J]. ANTI-CANCER DRUGS,2014,25(10):1129-1140.
APA Xing, Xiaofang.,Zhang, Lianhai.,Wen, Xianzi.,Wang, Xiaohong.,Cheng, Xiaojing.,...&Ji, Jiafu.(2014).PP242 suppresses cell proliferation, metastasis, and angiogenesis of gastric cancer through inhibition of the PI3K/AKT/mTOR pathway.ANTI-CANCER DRUGS,25(10),1129-1140.
MLA Xing, Xiaofang,et al."PP242 suppresses cell proliferation, metastasis, and angiogenesis of gastric cancer through inhibition of the PI3K/AKT/mTOR pathway".ANTI-CANCER DRUGS 25.10(2014):1129-1140.
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