Sensitivity of Ewing's sarcoma to TRAIL-induced apoptosis

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is able to kill transformed cells. We have studied the expression and functionality of the TRAIL apoptotic pathway in Ewing's sarcoma. We demonstrate that tumors from patients with Ewing's sarcoma express receptors TRAIL-R1 and -R2, Usi ng a panel of nine Ewing's sarcoma cell lines TRAIL could induce apoptosis in seven cell lines. Preincubation with interferon-gamma rendered the two r esistant cell lines sensitive. TRAIL was the most potent inducer of apoptos is when compared to Fas ligand or TNF. TRAIL-mediated apoptosis could be in hibited by various caspase-inhibitors. No difference in the surface express ion of TRAIL receptors was observed between sensitive and resistant cell li nes. Also, all cell lines had similar levels of expression of Flice-like in hibitory protein (FLIP) on immunoblot. However, the two resistant cell line s had only very low level expression of caspase 8 on RNA and protein level. In summary, we show that Ewing's sarcoma expresses receptors for TRAIL, an d that cells are exquisitely sensitive to TRAIL-mediated apoptosis. These r esults may warrant clinical trials with TRAIL in Ewing's sarcoma once the s afety of TRAIL for humans has been established.