mTOR Signaling is Involved in Indomethacin and Nimesulide Suppression of Colorectal Cancer Cell Growth via a COX-2 Independent Pathway
mTOR Signaling is Involved in Indomethacin and Nimesulide Suppression of Colorectal Cancer Cell Growth via a COX-2 Independent Pathway
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mTOR 信号转导参与吲哚美辛和尼美舒利通过 COX-2 独立途径抑制结直肠癌细胞生长
DOI：
10.1245/s10434-010-1268-9
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发表时间：
2011-02
影响因子：
3.7
通讯作者：
Jiang, Fo-Hu
中科院分区：
文献类型：
--
作者：
Zhang, Yan-Jie;Bao, Yu-Jie;Dai, Qiang;Yang, Wen-Yan;Cheng, Peng;Zhu, Li-Ming;Wang, Bi-Jun;Jiang, Fo-Hu
研究背景抑制哺乳动物雷帕霉素靶蛋白（mTOR）是一个有吸引力的抗肿瘤靶点，但其在环氧化酶-2（考克斯-2）抑制剂抑制结直肠癌（CRC）细胞生长中的作用尚不清楚。在此，我们分析了吲哚美辛（Indo，一种非选择性考克斯-2抑制剂）和尼美舒利（Nim，一种选择性考克斯-2抑制剂）在体外和体内对结直肠癌细胞中mTOR信号的影响，以确定这种作用对考克斯-2的依赖性。Western blot检测mTOR、p70 s6 K和4 EBP 1的表达，并检测细胞活力、细胞周期和凋亡情况。将HCT 116和SW 1116细胞注射到无胸腺裸鼠中以建立CRC异种移植物模型。在用Nim处理后，在该模型中评价肿瘤体积、mTOR信号传导和细胞凋亡。HT 29和SW 1116细胞也与尼姆转染后，与考克斯-2特异性小干扰RNA（siRNA），以评估依赖的考克斯-2对mTOR信号转导下drugtreatment. ResultsIndo和尼姆降低mTOR信号转导活性的CRC细胞，不同的考克斯-2在体外和体内的表达。此外，Indo和Nim可以降低考克斯-2沉默后，在CRC cells.ConclusionsmTOR信号转导参与Indo和Nim介导的抑制CRC生长通过考克斯-2的非依赖性途径。本研究揭示了考克斯-2抑制剂发挥其抗癌作用的新机制，并进一步强调在抗癌治疗中靶向mTOR信号传导。
BackgroundInhibition of mammalian target of rapamycin (mTOR) represents an attractive target for anticancer therapy, but its role in suppression of colorectal cancer (CRC) cell growth by cyclooxygenase-2 (COX-2) inhibitors is unclear. Here, we analyzed the effect of indomethacin (Indo, a nonselective COX-2 inhibitor) and nimesulide (Nim, a selective COX-2 inhibitor) on mTOR signaling in CRC cells in vitro and in vivo to determine the dependence of this effect on COX-2.MethodsHuman CRC cell lines with varying COX-2 expression levels were treated with Indo and Nim. Western blot test was performed to detect mTOR-related components (mTOR, p70s6 K, and 4EBP1), and cell viability, cell cycle, and apoptosis were assessed. HCT116 and SW1116 cells were injected into athymic nude mice to establish a CRC xenograft model. After treatment with Nim, tumor volume, mTOR signaling, and apoptosis were evaluated in this model. HT29 and SW1116 cells were also treated with Nim after transfection with COX-2-specific small interfering RNA (siRNA) to assess dependence of COX-2 on mTOR signaling under drug treatment.ResultsBoth Indo and Nim reduced mTOR signaling activity in CRC cells that differ in their COX-2 expression in vitro and in vivo. Additionally, Indo and Nim could reduce the mTOR signaling activity after COX-2 silencing in CRC cells.ConclusionsmTOR signaling is involved in Indo- and Nim-mediated suppression of CRC growth via a COX-2 independent pathway. This study unveils a novel mechanism through which COX-2 inhibitors exerts their anticancer effects and further emphasizes targeting mTOR signaling in anticancer therapy.
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DOI：
10.2174/138955707780859431
发表时间：
2007-05
期刊：
Mini reviews in medicinal chemistry
影响因子：
--
作者：
F. Sarkar;S. Adsule;Yiwei Li;S. Padhye
通讯作者：
F. Sarkar;S. Adsule;Yiwei Li;S. Padhye
影响因子：
--
作者：
S. Sudarsanam;Dale E. Johnson
通讯作者：
S. Sudarsanam;Dale E. Johnson
影响因子：
3.7
作者：
Zhang, Yan-Jie;Dai, Qiang;Fang, Jing-Yuan
通讯作者：
Fang, Jing-Yuan
影响因子：
2.8
作者：
Yan-jie Zhang;Shuliang Zhao;Xiao-qing Tian;Dan‐feng Sun;H. Xiong;Q. Dai;Xiao-Qiang Li;J. Fang
通讯作者：
Yan-jie Zhang;Shuliang Zhao;Xiao-qing Tian;Dan‐feng Sun;H. Xiong;Q. Dai;Xiao-Qiang Li;J. Fang
影响因子：
3.1
作者：
C. Czembirek;C. Eder-Czembirek;B. Erovic;D. Turhani;A. Spittler;E. Selzer;R. Pötter;D. Thurnher
通讯作者：
C. Czembirek;C. Eder-Czembirek;B. Erovic;D. Turhani;A. Spittler;E. Selzer;R. Pötter;D. Thurnher