Role of fibroblast growth factor receptor signaling in prostate cancer cell survival

Background: Expression of fibroblast growth factors (FGFs) is increased in a substantial fraction of human prostate cancers in vivo and in prostate ca ncer cell lines. Altered FGF signaling can potentially have a variety of ef fects, including stimulating cell proliferation and inhibiting cell death. To determine the biologic significance of altered FGF signaling in human pr ostate cancer, we disrupted signaling by expression of a dominant-negative (DN) FGF receptor in prostate cancer cell lines. Methods: PC-3, LNCaP, and DU145 prostate cancer cells were stably transfected with DN FGFR constructs , and LNCaP and DU145 cells were infected with a recombinant adenovirus exp ressing DN FGFR-1. The effect of DN FGFR-1 expression was assessed by colon y-formation assays, cell proliferation assays, flow cytometry, and cytogene tic analysis. Key regulators involved in the G(2)-to-M cell cycle transitio n were assessed by western blotting to examine cyclin B1 expression and by in vitro kinase assay to assess cdc2 kinase activity. Results: Stable trans fection of the DN FGFR-1 construct inhibited colony formation by more than 99% in all three cell lines. Infection of LNCaP and DU145 prostate cancer c ells with adenovirus expressing DN FGFR-1 led to extensive cell death withi n 48 hours. Flow cytometry and cytogenetic analysis revealed that the DN FG FR-1 receptor led to arrest in the G(2) phase of the cell cycle before cell death. Cyclin B1 accumulated in DN FGFR-1-infected LNCaP cells, but cdc2 k inase activity was decreased. Conclusions: These findings reveal an unexpec ted dependence of prostate cancer cells on FGF receptor signal transduction to traverse the G(2)/M checkpoint. The mechanism for the G(2) arrest is no t clear. Our results raise the possibility that FGF-signaling antagonists m ight enhance the cell death induced by other prostate cancer therapies.