Differential expression of members of the tumor necrosis factor alpha-related apoptosis-inducing ligand pathway in prostate cancer cells.
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 alpha-related apoptosis-inducing ligand (TRAIL) pathway, a newly identified and very effective member of tumor necrosis factor-alpha 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.
Sridhar
S
S
Medical College of Georgia, Section of Urology, Augusta, Georgia 30912, USA.
Ali
A A
AA
Liang
Y
Y
El Etreby
M F
MF
Lewis
R W
RW
Kumar
M V
MV
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015735:Mifepristone / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D053221:TNF-Related Apoptosis-Inducing Ligand; D013629:Tamoxifen / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D023041:Xenograft Model Antitumor Assays
D018931:Antineoplastic Agents, Hormonal; D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; C505640:Tnfrsf10b protein, mouse; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D013629:Tamoxifen; D015735:Mifepristone