Chemical sensitization and regulation of TRAIL-induced apoptosis in a panel of B-lymphocytic leukaemia cell lines
Chemical sensitization and regulation of TRAIL-induced apoptosis in a panel of B-lymphocytic leukaemia cell lines
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DOI：
10.1046/j.1365-2141.2003.04699.x
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发表时间：
2003-12-01
影响因子：
6.5
通讯作者：
Komada, Y
中科院分区：
文献类型：
--
作者：
Kang, J;Kisenge, RR;Komada, Y
肿瘤坏死因子相关凋亡诱导配体（TRAIL）能有效杀死肿瘤细胞，但对正常细胞无作用。我们研究了一组B淋巴细胞白血病细胞系对TRAIL的敏感性以及TRAIL诱导的凋亡信号通路。根据对TRAIL的敏感性，白血病细胞可分为三组：高度敏感组、中度敏感组和耐药组。TRAIL受体2（DR5）在传递凋亡信号中起重要作用。在敏感细胞和耐药细胞中，受TRAIL刺激时，DR5会内化到细胞质中，并在其中募集FAS相关死亡结构域蛋白（FADD）。然而，只有敏感细胞在受TRAIL刺激时，半胱天冬酶 - 8（caspase - 8）的活性形式会被募集到FADD上，且其caspase - 8活性增强。半胱天冬酶 - 8特异性抑制剂Z - IETD会削弱caspase - 8的激活，并完全消除TRAIL诱导的凋亡。这些结果表明，B淋巴细胞白血病细胞对TRAIL的耐药性是由于在caspase - 8激活水平上的负调控所致，并且caspase - 8激活是TRAIL诱导凋亡过程中不可或缺的环节。然而，在敏感细胞和耐药细胞中，FADD样白细胞介素 - 1β转换酶抑制蛋白（c - FLIPL）的表达情况相似，且在TRAIL刺激后均下调。有趣的是，在一些细胞系中，用环己酰亚胺（CHX）处理可增强或恢复对TRAIL的敏感性以及caspase - 8的活性。此外，用CHX处理后，X连锁凋亡抑制蛋白（XIAP）水平显著且迅速下降。在B淋巴细胞白血病细胞中，XIAP的下调可能是CHX处理后TRAIL敏感性增强或恢复的原因。
Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) effectively kills tumour cells but not normal cells. We investigated TRAIL sensitivity and the TRAIL-induced apoptosis signalling pathway in a panel of B-lymphocytic leukaemia cell lines. Depending upon TRAIL sensitivity, leukaemia cells could be divided into three groups: highly sensitive, moderately sensitive and resistant. TRAIL receptor-2 (DR5) plays an important role in transducing apoptosis signals. DR5 was internalized into the cytoplasm where it recruited FAS-associated death domain protein (FADD) under TRAIL stimulation in both sensitive and resistant cells. However, the active form of caspase-8 was recruited to FADD and only sensitive cells showed increased caspase-8 activity upon TRAIL stimulation. The caspase-8 specific inhibitor, Z-IETD, impaired caspase-8 activation and completely abrogated TRAIL-induced apoptosis. These results suggest that TRAIL resistance in B-lymphocytic leukaemia cells is due to negative regulation at the level of caspase-8 activation and that caspase-8 activation is an indispensable process in TRAIL-induced apoptosis. However, FADD-like interleukin-1 beta-converting enzyme inhibitory protein (c-FLIPL) was similarly expressed and down-regulated after TRAIL stimulation in both sensitive and resistant cells. Interestingly, in some cell lines, TRAIL sensitivity and caspase-8 activity was enhanced or restored with the treatment of cycloheximide (CHX). In addition, X-linked inhibitor of apoptosis (XIAP) levels decreased significantly and rapidly following treatment with CHX. Down-regulation of XIAP may be responsible for enhancement or restoration of TRAIL sensitivity after CHX treatment in B-lymphocytic leukaemia cells.