Killing Prostate Cancer Cells and Endothelial Cells with a VEGF- Triggered Cell Death Receptor

摘要

The goal of this project was to test a novel chimeric cell death receptor (termed R2Fas) that is triggered by vascular endothelial growth factor (VEGF), as a means to kill prostate cancer cells and vascular endothelial cells. The scope of this project involved: (i) creating adenoviral reagents to express the R2Fas receptor in prostate cancer cells and endothelial cells; (ii) determining if the R2Fas receptor kills cells in a VEGF-dependent manner; and (iii) identifying methods for increasing the killing activity of R2Fas. The major findings were: (i) we generated replication-defective adenoviral reagents to express R2Fas as well as control adenoviruses; (ii) we demonstrated that adenoviral-mediated expression of R2Fas in prostate cancer cells that overexpress VEGF activates apoptotic signaling and induces cell death; (iii) we demonstrated that adenoviral-mediated expression of R2Fas in human endothelial cell is non-toxic, but rendered the cells sensitive to killing when treated with VEGF; and (iv) we demonstrated that R2Fas-mediated apoptosis can be potentiated by addition of several pharmacologic agents, including camptothecin, etoposide, taxol, doxorubicin, cisplatin, and BisVIII.