Intracellular Mechanism and Clinical Significance of TRAIL in Prostate Cancer

摘要

We assessed the influence of sequential treatment of ionizing radiation followed by TRAIL on intracellular mechanisms of apoptosis of prostate tumor cells in vitro and in vivo. Prostate normal and cancer cells were exposed to irradiation and TRAIL. Four to six-week old athymic nude mice were injected s.c. with PC-3 tumor cells. Tumor bearing mice were exposed to irradiation and TRAIL, either alone or in combination, and tumor growth, apoptosis and survival of mice were examined. Irradiation significantly augmented TRAIL- induced apoptosis in prostate cancer cells through up-regulation of death receptor DR5, Bax and Bak, and induction of caspase activation. Dominant negative FADD and p53 siRNA inhibited the synergistic interaction between irradiation and TRAIL. The pretreatment of cells with irradiation followed by TRAIL significantly enhanced more apoptosis than single agent alone or concurrent treatment. Irradiation sensitized TRAIL-resistant LNCaP cells to undergo apoptosis. The sequential treatment of xenografted mice with irradiation followed by TRAIL induced apoptosis through activation of caspase-3, induction of Bax and Bak, and inhibition of Bcl-2, and completely eradicated the established tumors with enhanced survival of nude mice. The sequential treatment with irradiation followed by TRAIL can be used as a viable option to enhance the therapeutic potential of TRAIL in prostate cancer.