Analysis of mTOR inhibition-involved pathway in ovarian clear cell adenocarcinoma.
Analysis of mTOR inhibition-involved pathway in ovarian clear cell adenocarcinoma.
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DOI：
10.1267/ahc.10029
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发表时间：
2011-04-28
影响因子：
2.4
通讯作者：
Mikami M
中科院分区：
文献类型：
--
作者：
Harasawa M;Yasuda M;Hirasawa T;Miyazawa M;Shida M;Muramatsu T;Douguchi K;Matsui N;Takekoshi S;Kajiwara H;Yoshiyuki Osamura R;Mikami M
本研究以人卵巢透明细胞腺癌（CCA）细胞株为研究对象，探讨雷帕霉素靶蛋白（mTOR）-缺氧诱导因子-1（HIF-1）通路的作用机制。依维莫司（雷帕霉素的衍生物）处理的细胞和未处理的细胞在mTOR表达方面没有显示出任何差异。但磷酸化mTOR（p-mTOR）的表达在处理的细胞中显著降低，并且mTOR下游区域的mTOR相关因子如磷酸化-4 E-BP 1（p-4 E-BP 1）、HIF-1α和血管内皮生长因子（VEGF）的表达显著降低。药物对HIF-1α降解系统的影响分析显示，在处理的细胞中von-Hippel Lindau（VHL）表达增加。在处理的细胞中还显示了参与凋亡的关键因子之一的切割的caspase-3的增加。在下一步中，使用植入RMG-1细胞的裸鼠，在口服给予依维莫司的7只小鼠中的4只中证实肿瘤大小减小。结果表明，依维莫司给药不仅通过下调p-mTOR，而且通过VHL降解HIF-1α和通过切割的caspase-3诱导凋亡，有助于CCA的抗肿瘤治疗。
This study was designed to clarify the mechanism of the mammalian target of rapamycin (mTOR)-hypoxia inducible factor-1 (HIF-1) pathway using the cultured cell strain derived from human ovarian clear cell adenocarcinoma (CCA). Everolimus (a derivative of rapamycin)-treated cells and non-treated cells did not show any difference in mTOR expression. But, phosphorylated-mTOR (p-mTOR) expression significantly decreased in the treated cells, and mTOR-related factors such as phosphorylated-4E-BP1 (p-4E-BP1), HIF-1α, and vascular endothelial growth factor (VEGF) in the downstream region of mTOR revealed a marked decrease in expression. The analysis of influences of the drug on the HIF-1α degradation system showed an increase in von-Hippel Lindau (VHL) expression in the treated cells. Increase of cleaved caspase-3, one of key factors involved in apoptosis, was also shown in the treated cells. In the next step, using nude mice implanted with RMG-1 cells, a decrease in tumor size was demonstrated in 4 of the 7 mice which were orally administered with everolimus. As a result, it was suggested that everolimus administration would be helpful as an anti-tumor therapy for CCA not only via down-regulation of p-mTOR but also degradation of HIF-1α by VHL and induction of apoptosis by cleaved caspase-3.
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影响因子：
3.3
作者：
Osada, Ryosuke;Horiuchi, Akiko;Konishi, Ikuo
通讯作者：
Konishi, Ikuo
影响因子：
2.4
作者：
Miyajima K;Takekoshi S;Itoh J;Kakimoto K;Miyakoshi T;Osamura RY
通讯作者：
Osamura RY
DOI：
10.1073/pnas.92.11.4947
发表时间：
1995-05-23
影响因子：
11.1
作者：
CHEN, J;ZHENG, XF;SCHREIBER, SL
通讯作者：
SCHREIBER, SL
DOI：
10.1111/j.1525-1438.2006.00310.x
发表时间：
2006-01-01
影响因子：
4.8
作者：
Jiang, H;Feng, Y
通讯作者：
Feng, Y
影响因子：
64.5
作者：
Beuvink, I;Boulay, A;Thomas, G
通讯作者：
Thomas, G