Sensitivity of prostate cells to TRAIL-induced apoptosis increases with tumor progression: DR5 and caspase 8 are key players

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Abstract
BACKGROUND As advanced prostate cancers are resistant to currently available chemotherapies, we evaluated the cytotoxic effect of TNF‐related apoptosis‐inducing ligand (TRAIL) and characterized the involvement of its five receptors DR4, DR5, DcR1, DcR2, and osteoprotegerin (OPG) and of the death‐inducing signaling complex (DISC)‐forming proteins caspase 8 and c‐FLIP in prostate cell lines. METHODS We used six prostate cell lines, each corresponding to a particular stage in prostate tumorigenesis, and analyzed TRAIL sensitivity in relation to TRAIL receptors' expression. RESULTS TRAIL sensitivity was correlated with tumor progression and DR5 expression levels and apoptosis was exclusively mediated by DR5. DcR2 was significantly more abundant in tumor cells than in non‐neoplastic ones and may contribute to partial resistance to TRAIL in some prostate tumor cells. Conversely, non‐tumoral cells secreted high levels of OPG, which can protect them from apoptosis. Finally, caspase 8 expression levels were as DR5 directly correlated to TRAIL sensitivity in prostate tumor cells. CONCLUSION TRAIL‐induced apoptosis is closely related to the balanced expression of its different receptors in prostate cancer cells and their modulation could be of potential clinical value for advanced tumor treatment. Prostate 66: 987–995, 2006.