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Role of Antiapoptotic Proteins in Tumor Necrosis Factor-related Apoptosis-inducing Ligand and Cisplatin-augmented Apoptosis¹

Departments of Surgery [J. H. K., M. A., Y. J. L.] and Pathology [A. L.], University of Pittsburgh, Pittsburgh, Pennsylvania, 15213

Purpose and Experimental Design: The purpose of this study was to examine the effect of combined treatment with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and cisplatin in human head and neck squamous cell carcinoma. HNSCC-6 cells were treated with 0.1–1 µg/ml TRAIL and/or 1–10 µg/ml cisplatin for 24 h.

Results: TRAIL alone or cisplatin alone caused minimal cytotoxicity. The combination of TRAIL and cisplatin synergistically enhanced apoptotic death, caspase-8 and caspase-3 activation, as well as poly(ADP-ribose) polymerase cleavage. However, the total cellular levels and the surface expression of TRAIL receptor proteins, such as death receptors 4 and 5 and decoy receptors 2 and 1, were not significantly changed by treatment with TRAIL and cisplatin. Interestingly, the level of the short form of Fas-associated death domain-like interleukin-1ß-converting enzyme-inhibitory protein (FLIP_S) but not the long form of Fas-associated death domain-like interleukin-1ß-converting enzyme-inhibitory protein was reduced through cleavage. Benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone a caspase-3 inhibitor, blocked the cleavage of FLIP_S and caspase-3 activation. Overexpression of FLIP_S protected cells from apoptotic death and FLIP_S cleavage during treatment with TRAIL in combination with cisplatin.

Conclusions: These results suggest that caspase-3 is responsible for FLIP_S cleavage, and the cleavage of FLIP_S is one of facilitating factors for TRAIL-induced apoptotic death.

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