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  • Title: Role of antiapoptotic proteins in tumor necrosis factor-related apoptosis-inducing ligand and cisplatin-augmented apoptosis.
    Author: Kim JH, Ajaz M, Lokshin A, Lee YJ.
    Journal: Clin Cancer Res; 2003 Aug 01; 9(8):3134-41. PubMed ID: 12912965.
    Abstract:
    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 micro g/ml TRAIL and/or 1-10 micro g/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-1beta-converting enzyme-inhibitory protein (FLIP(S)) but not the long form of Fas-associated death domain-like interleukin-1beta-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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