子宫内膜癌
癌症研究
自分泌信号
细胞凋亡
医学
癌症
肝细胞生长因子
肿瘤科
内科学
生物
受体
生物化学
作者
Yuhei Kogata,Tomohito Tanaka,Yoshihiro Ono,Masami Hayashi,Yoshito Terai,Masahide Ohmichi
出处
期刊:Oncotarget
[Impact Journals, LLC]
日期:2018-04-27
卷期号:9 (32): 22769-22784
被引量:13
标识
DOI:10.18632/oncotarget.25232
摘要
// Yuhei Kogata 1 , Tomohito Tanaka 1 , Yoshihiro J. Ono 1 , Masami Hayashi 1 , Yoshito Terai 1 and Masahide Ohmichi 1 1 Department of Obstetrics and Gynecology, Osaka Medical College, Takatsuki, Japan Correspondence to: Tomohito Tanaka, email: gyn123@osaka-med.ac.jp Keywords: endometrial cancer; foretinib; p53; apoptosis Received: September 08, 2017 Accepted: April 06, 2018 Published: April 27, 2018 ABSTRACT Objective: Foretinib (GSK1363089 or XL880), which is an oral multikinase inhibitor developed to primarily target the hepatocyte growth factor (HGF)/Met signaling pathway, has shown anti-tumor effects against some cancers in preclinical and clinical studies. Results: HGF/Met signaling in endometrial cancer cell lines was stimulated in an autocrine manner, and was essential for cell survival. Inhibiting the HGF/Met signaling with foretinib induced p53-dependent apoptosis in endometrial cancer cell lines in vitro . Foretinib also showed significant anti-cancer effects in vivo in experiments using cell tumor xenografts. p53 mutations were observed in 37 (10.8%) of 344 endometrial cancer specimens. Conclusion: The HGF/Met-MAPK/PI3K pathway in endometrial cancer is activated by HGF in an autocrine manner. Foretinib induces an anti-cancer effect through the anti-phosphorylation of Met, which results in the induction of p53-dependent apoptosis; foretinib was found to exert greater anti-cancer activity in endometrial cancer specimens with wild-type p53 than in specimens with p53 mutations. Our immunochemical analysis revealed that foretinib-induced p53-dependent apoptosis can be expected to have therapeutic potential in approximately 90% of endometrial cancer patients. Methods: We evaluated the HGF/Met signaling pathway in endometrial cancer cell lines and assessed the anti-cancer effects of foretinib using in vitro and in vivo experimental models. Furthermore, endometrial cancer specimens were subjected to an immunohistochemical analysis.
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