期刊
ONCOGENE
卷 31, 期 10, 页码 1217-1227出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2011.314
关键词
SRC; NEDD9; Aurora; drug; mitosis; attachment
资金
- Army Materiel Command [DOD W81XWH-07-1-0676]
- State of Pennsylvania
- Ovarian Cancer Research Fund
- Ovarian SPORE [P50 CA083638]
- Commonwealth of Pennsylvania
- Greenberg Fund
- NCI [CA06927]
- Pew Charitable Fund
- Fox Chase Cancer Center
- [R01-CA63366]
- [R01-CA113342]
- [R01-CA140323]
- [R01-GM86877]
- [R01-CA136596]
- [R01-CA151374]
- [R01-CA50633]
Increased activity of SRC family kinases promotes tumor invasion and metastasis, and overexpression of the mitotic regulator Aurora kinase A (AURKA) drives tumor aneuploidy and chromosomal instability. These functions nominate SRC and AURKA as valuable therapeutic targets for cancer, and inhibitors for SRC and Aurora kinases are now being used in the clinic. In this study, we demonstrate potent synergy between multiple inhibitors of Aurora and SRC kinases in ovarian and colorectal cancer cell lines, but not in normal ovarian epithelial cell lines. Combination of Aurora and SRC inhibitors selectively killed cells that have undergone a preceding aberrant mitosis, and was associated with a postmitotic reattachment defect, and selective removal of aneuploid cell populations. Combined inhibition of Aurora kinase and SRC potentiated dasatinib-dependent loss of activated (Y416-phosphorylated) SRC. SRC and AURKA share a common interaction partner, NEDD9, which serves as a scaffolding protein with activities in cell attachment and mitotic control, suggesting SRC and AURKA might interact directly. In vitro, we observed physical interaction and mutual cross-phosphorylation between SRC and AURKA that enhanced SRC kinase activity. Together, these findings suggest that combination of SRC and Aurora-targeting inhibitors in the clinic may be a productive strategy. Oncogene (2012) 31, 1217-1227; doi:10.1038/onc.2011.314; published online 25 July 2011
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据