Src tyrosine kinase promotes survival and resistance to chemotherapeutics in a mouse ovarian cancer cell line

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Abstract

The vast majority of ovarian cancers originate in the ovarian surface epithelium. Unfortunately, there is a lack of appropriate animal models for ovarian cancer research. Spontaneously transformed mouse ovarian surface epithelial cells may provide a faithful animal model for human ovarian cancer. One such cell line (ID8) has been partially characterized. ID8 cells demonstrate constitutive Src tyrosine kinase activation with resulting phosphatidylinositol-3-kinase activation and Akt and forkhead phosphorylation. In addition, focal adhesion kinase is constitutively phosphorylated at tyrosine 925, a Src phosphorylation site, resulting in increased Ras activation. These features are common to human ovarian cancer cell lines. Inhibition of Src enhances the cell killing effects of both paclitaxel and cisplatinum. Finally, Src inhibition restores sensitivity of a drug resistant ID8 cell line. The ID8 mouse ovarian cancer cell line presents new opportunities to study ovarian cancer progression and pre-therapeutic trials in an immune competent background.

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Methods

Reagents. All liquid media were purchased from Life Technologies (Grand Island, NY). A Src specific antibody (clone 327) was purchased from Oncogene Science (Cambridge, MA). A phospho-Src specific antibody that recognizes tyrosine 418 phosphorylated Src was purchased from Biosource International (Camarillo, CA). A Ras activation assay kit and FAK antibodies were from Upstate Biotechnology (Lake Placid, NY). Akt, phospho-Akt, and phospho-FKHR were from Cell Signaling (Beverly, MA). A

ID8 cells express constitutively active Src tyrosine kinase

Because Src tyrosine kinase has been reported to be overexpressed and activated in both human ovarian cancer cell lines and late stage ovarian cancers [8], Src protein and kinase activity were determined in ID8 mouse ovarian cancer cells and ID8 cell derived tumors. ID8 cells express a significant amount of Src protein in comparison to early passage human ovarian surface epithelial cells (Fig. 1A). ID8 mouse ovarian cancer cells from serum-starved cultures express comparable levels of Src

Acknowledgements

This research was supported by National Institutes of Health Grants HD36013 (Chris Taylor), CA50616 (Paul Terranova) and Department of Defense Grant OC990038 (Chris Taylor).

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