The pleiotropic effect of TRAIL on tumor-like synovial fibroblasts from rheumatoid arthritis patients is mediated by caspases
The pleiotropic effect of TRAIL on tumor-like synovial fibroblasts from rheumatoid arthritis patients is mediated by caspases
复制标题
DOI：
10.1038/cdd.2009.38
复制
发表时间：
2009-09-01
影响因子：
12.4
通讯作者：
Hahne, M.
中科院分区：
文献类型：
--
作者：
Audo, R.;Combe, B.;Hahne, M.
肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）作为治疗肿瘤的可能的治疗试剂已经获得了很多关注，因为TRAIL最初被描述为特异性地在癌细胞中诱导凋亡，而不是在正常细胞中。类风湿性关节炎（RA）患者的成纤维细胞样滑膜细胞（FLS）表现出肿瘤样特征，我们之前已经描述了TRAIL仅在RA FLS的一个子集中诱导凋亡，但在存活细胞中诱导增殖。该观察结果对应于在原代人肿瘤细胞上观察到的TRAIL的多效性作用。在这里，我们描述了PI 3激酶/Akt信号通路，而不是MAP激酶ERK和p38，通过调节细胞存活调节因子p21，XIAP，Mcl-1和RIP的表达来保护RA FLS免受TRAIL诱导的凋亡。此外，我们发现不仅TRAIL诱导的细胞凋亡，而且TRAIL触发的RA FLS增殖是由半胱天冬酶介导的，其中半胱天冬酶8起着至关重要的作用。发现TRAIL诱导p21和p27的降解是半胱天冬酶依赖性的，但不依赖于ERK、p38和PI 3激酶/Akt信号通路。在定义基于施用TRAIL的治疗策略时，必须考虑TRAIL触发的增殖和凋亡共享细胞内途径的发现。Cell Death and Differentiation（2009）16，1227-1237; doi：10.1038/cdd.2009.38; 2009年5月1日在线发表
The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has gained much attention as a possible therapeutic reagent for the treatment of tumors, as TRAIL was originally described to induce apoptosis specifically in cancer cells, but not in normal cells. Fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) patients exhibit tumor-like features and we have described earlier that TRAIL induces apoptosis only in a subset of RA FLS, but an induction of proliferation in the surviving cells. This observation corresponds to the pleiotropic effects of TRAIL observed on primary human tumor cells. Here, we describe that the PI3 kinase/Akt-signaling pathway, but not that of the MAP kinases ERK and p38, protects RA FLS from TRAIL-induced apoptosis by modulating the expression of the cell survival regulators p21, XIAP, Mcl-1 and RIP. Moreover, we found that not only TRAIL-induced apoptosis, but also TRAIL-triggered proliferation in RA FLS is mediated by caspases with a crucial role for caspase 8. TRAIL was found to induce degradation of p21 and p27 that was caspase-dependent, but independent of the ERK, p38 and PI3 kinase/Akt-signaling pathways. The finding that TRAIL-triggered proliferation and apoptosis share intracellular routes has to be taken in consideration in defining therapeutic strategies on the basis of the administration of TRAIL. Cell Death and Differentiation (2009) 16, 1227-1237; doi: 10.1038/cdd.2009.38; published online 1 May 2009