Sensitization of osteosarcoma cells to death receptor-mediated apoptosis by HDAC inhibitors through downregulation of cellular FLIP
Sensitization of osteosarcoma cells to death receptor-mediated apoptosis by HDAC inhibitors through downregulation of cellular FLIP
复制标题
DOI：
10.1038/sj.cdd.4401507
复制
发表时间：
2005-01-01
影响因子：
12.4
通讯作者：
Yonehara, S
中科院分区：
文献类型：
--
作者：
Watanabe, K;Okamoto, K;Yonehara, S
Fas介导的细胞凋亡在消除体内肿瘤细胞方面发挥着重要作用，但一些肿瘤来源的细胞对此机制有抵抗力。在这里，我们发现，用组蛋白脱乙酰酶 (HDAC) 抑制剂 FR901228 治疗，通过下调细胞 FLIP（细胞 FLICE 抑制蛋白）的表达，使 Fas 抗性骨肉瘤细胞系对 Fas 介导的细胞凋亡敏感，FLIP 是 Fas 介导的 caspase-8 激活的抑制剂。此外，通过使用 FLIP 特异性 RNA 干扰抑制 FLIP 表达，在 Fas 抗性骨肉瘤细胞中也诱导了对 Fas 介导的细胞凋亡的敏感性。包括 FR901228 在内的 HDAC 抑制剂被证明可以通过抑制 FLIP mRNA 的生成来诱导细胞 FLIP 的下调，而不是刺激蛋白质或 mRNA 水平的降解，并且这种抑制与从头蛋白质合成无关。这些结果清楚地表明，一些肿瘤细胞通过表达细胞FLIP表现出对死亡受体介导的细胞凋亡具有抵抗力的表型，并且HDAC抑制剂通过直接下调细胞FLIP mRNA来使这种抵抗性肿瘤细胞敏感。
Fas-mediated apoptosis plays an important role in elimination of tumor cells in vivo, but some tumor-derived cells are resistant to this mechanism. Here, we show that treatment with the histone deacetylase (HDAC) inhibitor FR901228 renders Fas-resistant osteosarcoma cell lines sensitive to Fas-mediated apoptosis by downregulating expression of cellular FLIP (cellular FLICE-inhibitory protein), an inhibitor of Fas-mediated activation of caspase-8. Moreover, sensitization to Fas-mediated apoptosis was also induced in Fas-resistant osteosarcoma cells by suppressing FLIP expression using FLIP-specific RNA interference. HDAC inhibitors including FR901228 were shown to induce downregulation of cellular FLIP through inhibiting generation of FLIP mRNA, rather than stimulating degradation at either protein or mRNA level, and the inhibition was independent of de novo protein synthesis. These results clearly indicate that some tumor cells exhibit a phenotype resistant to death receptor-mediated apoptosis by expressing cellular FLIP, and that HDAC inhibitors sensitize such resistant tumor cells by directly downregulating cellular FLIP mRNA.