TAK1 kinase determines TRAIL sensitivity by modulating reactive oxygen species and cIAP.
TAK1 kinase determines TRAIL sensitivity by modulating reactive oxygen species and cIAP.
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DOI：
10.1038/onc.2009.110
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发表时间：
2009-06-11
期刊：
影响因子：
8
通讯作者：
Ninomiya-Tsuji, J.
中科院分区：
文献类型：
--
作者：
Morioka, S.;Omori, E.;Kajino, T.;Kajino-Sakamoto, R.;Matsumoto, K.;Ninomiya-Tsuji, J.
tnf相关凋亡诱导配体（TRAIL）是几种癌细胞中有效的细胞死亡诱导剂，但许多细胞对TRAIL具有抗性。决定trail杀伤敏感性的机制仍然难以捉摸。在这里，我们报道了TAK1激酶的缺失极大地增加了角化细胞、成纤维细胞以及癌细胞在TRAIL刺激后caspase-3的激活和诱导细胞死亡。虽然TAK1激酶参与NF-κB通路，但NF-κB的消融并未改变对TRAIL的敏感性。我们发现，当TAK1被删除时，TRAIL可以诱导活性氧（ROS）的积累。此外，我们发现TAK1缺失诱导trail依赖的cIAP下调，从而增强caspase-3的激活。这些结果表明，TAK1缺失通过ROS激活caspase和下调cIAP来促进trail诱导的细胞死亡。因此，抑制TAK1可能是增加TRAIL敏感性的有效途径。
TNF-related apoptosis-inducing ligand (TRAIL) is a potent inducer of cell death in several cancer cells, but many cells are resistant to TRAIL. The mechanism that determines sensitivity to TRAIL-killing is still elusive. Here we report that deletion of TAK1 kinase greatly increased activation of caspase-3 and induced cell death following TRAIL stimulation in keratinocytes and fibroblasts as well as cancer cells. Although TAK1 kinase is involved in NF-κB pathway, ablation of NF-κB did not alter sensitivity to TRAIL. We found that TRAIL could induce accumulation of reactive oxygen species (ROS) when TAK1 was deleted. Furthermore, we found that TAK1 deletion induces TRAIL-dependent downregulation of cIAP, which enhances activation of caspase-3. These results demonstrate that TAK1 deletion facilitates TRAIL-induced cell death by activating caspase through ROS and downregulation of cIAP. Thus, inhibition of TAK1 can be an effective approach to increase TRAIL sensitivity.
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