The Role of Src Tyrosine Kinase Signaling Networks in the Development and Progression of Ovarian Cancer in a Mouse Model
Abstract
Ovarian cancer is among the most common and deadly malignancies in women, accounting for nearly 15,000 deaths per year in the United States. We have developed a mouse model of ovarian cancer, which will allow for new studies into the biochemical changes that occur in the tumorigenic process. We have determined that Src tyrosine kinase is over expressed and constitutively activated in these mouse ovarian cancer cells. This leads to constitutive activation of downstream kinases such as phosphatidylinositol-3-kinase (PI3-kinase) and focal adhesion kinase (FAK). Pharmacologic inhibition of Src suppresses cell migration, alters localization of FAK, decreases protein tyrosine kinase phosphorylation, inhibits the PI3-kinase/Akt survival pathway and enhances the cell killing effects of two different classes of chemotherapeutics, taxol, and cisplatin, commonly used chemotherapeutic agents in women with ovarian cancer. Combination treatment of mouse ovarian cancer cells with Src inhibition and taxol activates a cell-killing pathway involving caspase 3 that is not activated by either treatment alone. We have also generated taxol resistant mouse ovarian cancer cells. Pharmacologic inhibition of Src restores taxol sensitivity to taxol resistant cells. Thus it appears that Src provides a potential new target for small molecule, targeted, combinatorial chemotherapy.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2002
- Accession Number
- ADA409636
Entities
People
- Christopher C. Taylor
- Ting Chen
Organizations
- Georgetown University