Tumor necrosis factor-related apoptosis-inducing ligand-mediated proliferation of tumor cells with receptor-proximal apoptosis defects
Tumor necrosis factor-related apoptosis-inducing ligand-mediated proliferation of tumor cells with receptor-proximal apoptosis defects
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DOI：
10.1158/0008-5472.can-04-4278
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发表时间：
2005-09-01
期刊：
影响因子：
11.2
通讯作者：
Jeremias, I
中科院分区：
文献类型：
--
作者：
Baader, E;Toloczko, A;Jeremias, I
肿瘤坏死因子相关凋亡诱导配体（Tumor necrosis factor-related apoptosis-inducing ligand， TRAIL）在动物实验中可诱导肿瘤细胞凋亡而无毒性，可能成为未来治疗癌症的细胞毒性药物。我们最近报道，与细胞凋亡相反，TRAIL在某些肿瘤细胞中介导肿瘤细胞存活和增殖。我们研究了TRAIL对18个细胞系和53个原发白血病细胞的影响，并将这些肿瘤细胞分为4组：TRAIL、抗dr4和抗dr5诱导A组细胞凋亡，而TRAIL对0组细胞无影响，P组细胞介导增殖。让我们惊讶的是，TRAIL诱导AP组细胞同时发生凋亡和增殖。超过20%的测试细胞属于P组，即使存在某些细胞毒性药物，但不存在核因子κ b抑制剂，也显示trail介导的增殖。转染b细胞白血病/淋巴瘤蛋白2将A组细胞转化为0组细胞，而转染fas相关的死亡结构域多肽（FADD）如白细胞介素-1转换酶抑制蛋白（FLIP）将其转化为AP组细胞。缺失caspase8或转染显性阴性FADD将A组细胞转化为P组细胞。综上所述，我们的数据表明，增殖是TRAIL对肿瘤细胞的一种常见影响，这与死亡诱导信号复合物水平上的受体近端凋亡缺陷有关，在使用TRAIL进行抗肿瘤治疗时应加以预防。
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) might represent a future cytotoxic drug to treat cancer as it induces apoptosis in tumor cells without toxicity in animal trials. We recently described that in contrast to apoptosis, TRAIL mediates tumor cell survival and proliferation in certain tumor cells. Here we studied the effect of TRAIL on 18 cell lines and 53 primary leukemia cells and classified these tumor cells into four groups: TRAIL, anti-DR4 or anti-DR5 induced apoptosis in group A cells, whereas they had no effect on group 0 cells and mediated proliferation in group P cells. To our surprise, TRAIL induced simultaneous apoptosis and proliferation in group AP cells. More than 20% of all cells tested belonged to group P and showed TRAIL-mediated proliferation even in the presence of certain cytotoxic drugs but not inhibitors of nuclear factor-kappa B. Transfection with B-cell leukemia/lymphoma protein 2 transformed group A cells into group 0 cells, whereas transfection with Fas-associated polypeptide with death domain (FADD)like interleukin-1-converting enzyme -inhibitory protein (FLIP) transformed them into group AP cells. Loss of caspase8 or transfection of dominant-negative FADD transformed group A cells into group P cells. Taken together, our data suggest that proliferation is a frequent effect of TRAIL on tumor cells, which is related to receptor-proximal apoptosis defects at the level of the death-inducing signaling complex and should be prevented during antitumor therapy with TRAIL.