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Differential Expression of Members of the Tumor Necrosis Factor -related Apoptosis-inducing Ligand Pathway in Prostate Cancer Cells

Medical College of Georgia, Section of Urology, Augusta, Georgia 30912 [S. S., Y. L., M. F. E. E., R. W. L., M. V. K.]; Veterans Administration Medical Center, Augusta, Georgia 30904 [M. V. K.]; and Division of Endocrinology, University of Arkansas Medical School, Little Rock, Arkansas 72205 [A. A. A.]

Androgen ablation therapy induces apoptosis only in androgen-sensitive prostate cancer cells; therefore, other cytotoxic drugs are being used to induce apoptosis in androgen-refractory cells. Mifepristone, an antiprogestin used individually or together with the antiestrogen Tamoxifen, has been recommended for induction of cell death and treatment of several hormonal cancers. However, little is known about the mechanism of action of these drugs in prostate cancer. Therefore, we investigated the effect of Mifepristone on the tumor necrosis factor -related apoptosis-inducing ligand (TRAIL) pathway, a newly identified and very effective member of tumor necrosis factor- family. Mifepristone and Tamoxifen induced significant expression of death receptors in prostate cancer cells in vitro and in xenografts. However, Mifepristone in combination with Tamoxifen did not increase prostate cancer cell death compared with their individual values. The involvement of the TRAIL pathway was further confirmed by the activation of caspase-8 in Mifepristone-treated cells. This was followed by truncation of Bid, confirming that Mifepristone activates the TRAIL pathway. This knowledge is being used to design a combination treatment of TRAIL and Mifepristone to induce significant apoptosis in prostate cancer cells.

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