このエントリーをはてなブックマークに追加
ID 49564
FullText URL
Author
Hao, Hui-fang
Takaoka, Munenori
Bao, Xiao-hong
Wang, Zhi-gang
Tomono, Yasuko
Sakurama, Kazufumi
Ohara, Toshiaki
Fukazawa, Takuya
Yamatsuji, Tomoki
Naomoto, Yoshio
Abstract
Peritoneal dissemination is one of the most terrible types of colorectal cancer progression. Focal adhesion kinase (FAK) plays a crucial role in the biological processes of cancer, such as cell attachment, migration, proliferation and survival, all of which are essential for the progression of peritoneal dissemination. Since we and other groups have reported that the inhibition of FAK activity exhibited a potent anticancer effect in several cancer models, we hypothesized that TAE226, a novel ATP-competitive tyrosine kinase inhibitor designed to target FAK, can prevent the occurrence and progression of peritoneal dissemination. In vitro, TAE226 greatly inhibited the proliferation and migration of HCT116 colon cancer cells, while their adhesion on the matrix surface was minimally inhibited when FAK activity and expression was suppressed by TAE226 and siRNA. In vivo, when HCT116 cells were intraperitoneally inoculated in mice, the cells could attach to the peritoneum and begin to grow within 24 h regardless of the pretreatment of cells with TAE226 or FAK-siRNA, suggesting that FAK is not essential, at least for the initial integrin-matrix contact. Interestingly, the treatment of mice before and after inoculation significantly suppressed cell attachment to the peritoneum. Furthermore, oral administration of TAE226 greatly reduced the size of disseminated tumors and prolonged survival in tumor-bearing mice. Taken together, a possible strategy for inhibiting peritoneal dissemination by targeting FAK with TAE226 appears to be applicable through anti-proliferative and anti-invasion/anti-migration mechanisms.
Keywords
Focal adhesion kinase
TAE226
Peritoneal dissemination
Prolonged survival
Anti-proliferation
Colon cancer
Published Date
2012-07-13
Publication Title
Biochemical and Biophysical Research Communications
Volume
volume423
Issue
issue4
Publisher
Academic Press Inc Elsevier Science
Start Page
744
End Page
749
ISSN
0006-291X
NCID
AA00564395
Content Type
Journal Article
Official Url
http://dx.doi.org/10.1016/j.bbrc.2012.06.030
language
英語
Copyright Holders
(C) 2012 Elsevier Inc. All rights reserved.
File Version
author
Refereed
True
DOI
Web of Sience KeyUT