Abstract

The standard therapies for localized PCa include radiation and surgery which show great promise in treatment of early stage cancers. For those men who develop advanced PCa, androgen ablation therapy along with chemotherapy is the current standard of care. Unfortunately, these therapies do not provide long term survival; the median survival for men with advanced PCa is two years. The major obstacles posed by advanced PCa are androgen independence and chemoresistant bone metastasis. A number of chemotherapeutic regimens have been used in the past to treat advanced PCa, but showed no increase in the survival benefit. Currently, the chemotherapeutic of choice used to treat men with advanced PCa is docetaxel. Initial treatments with docetaxel provide an increase in the survival benefit in men, however, long term treatment with docetaxel produces a chemoresistant PCa. In order to prevent chemoresistance, a better understanding to the molecular events leading to docetaxel resistance in PC needs to be elucidated. I hypothesized that components of the bone microenvironment, such as type I collagen mediate the chemoresistance of PCa. To test this hypothesis I utilized the bone metastasis derived PCa cell line, PC3, and plated these cells on type I collagen. The primary type I collagen binding integrin expressed on PC3 cells is α₂β₁. When binding of this integrin is inhibited, there is a significant reduction in PC3 cells binding to type I collagen matrix. Blocking of the α₂β ₁ integrin of PC3 cells plated on type I collagen matrix showed a significant increase in sensitivity to docetaxel. Docetaxel dose-response curves of PC3 cells showed that PC3 cells adhered to fibronectin showed the greatest reduction in docetaxel sensitivity. I showed that reduced chemosensitivity of PC3 cells adhered to fibronectin is dependent on Akt activation, assessed by cell viability and caspase activation analysis. Western blot analysis of p-Akt in PC3 cells adhered different substrates, show that Akt is activated the greatest in PC3 cells adhered to type I collagen. We conclude that the chemoresistance of PCa to docetaxel is influenced differently by the adhesion of PCa cells to components of bone microenvironment.