Kontny H U, Hämmerle K, Klein R, Shayan P, Mackall C L, Niemeyer C M
Children's Hospital of the Albert-Ludwigs-University, Freiburg, Germany.
Cell Death Differ. 2001 May;8(5):506-14. doi: 10.1038/sj.cdd.4400836.
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. Using a panel of nine Ewing's sarcoma cell lines TRAIL could induce apoptosis in seven cell lines. Preincubation with interferon-gamma rendered the two resistant cell lines sensitive. TRAIL was the most potent inducer of apoptosis when compared to Fas ligand or TNF. TRAIL-mediated apoptosis could be inhibited by various caspase-inhibitors. No difference in the surface expression of TRAIL-receptors was observed between sensitive and resistant cell lines. Also, all cell lines had similar levels of expression of Flice-like inhibitory protein (FLIP) on immunoblot. However, the two resistant cell lines 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, and that cells are exquisitely sensitive to TRAIL-mediated apoptosis. These results may warrant clinical trials with TRAIL in Ewing's sarcoma once the safety of TRAIL for humans has been established.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）能够杀死转化细胞。我们研究了TRAIL凋亡途径在尤因肉瘤中的表达及功能。我们证明，尤因肉瘤患者的肿瘤表达TRAIL-R1和-R2受体。使用一组9种尤因肉瘤细胞系，TRAIL可诱导7种细胞系发生凋亡。用γ干扰素预孵育可使两种耐药细胞系变得敏感。与Fas配体或TNF相比，TRAIL是最有效的凋亡诱导剂。TRAIL介导的凋亡可被多种半胱天冬酶抑制剂抑制。在敏感和耐药细胞系之间未观察到TRAIL受体表面表达的差异。此外，所有细胞系在免疫印迹上的类Fas相关死亡结构域样抑制蛋白（FLIP）表达水平相似。然而，两种耐药细胞系在RNA和蛋白质水平上半胱天冬酶8的表达水平极低。总之，我们表明尤因肉瘤表达TRAIL受体，并且细胞对TRAIL介导的凋亡极为敏感。一旦确定TRAIL对人类的安全性，这些结果可能为在尤因肉瘤中使用TRAIL进行临床试验提供依据。
