Chemotherapy overcomes TRAIL-R4-mediated TRAIL resistance at the DISC level
Chemotherapy overcomes TRAIL-R4-mediated TRAIL resistance at the DISC level
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DOI：
10.1038/cdd.2010.144
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发表时间：
2011-04-01
影响因子：
12.4
通讯作者：
Micheau, O.
中科院分区：
文献类型：
--
作者：
Morizot, A.;Merino, D.;Micheau, O.
肿瘤坏死因子相关的凋亡诱导配体或载脂蛋白2L(Apo2L/TRAIL)通过与肿瘤细胞表达的两种膜结合受体TRAIL-R1或TRAIL-R2诱导细胞凋亡，是一种很有前途的抗癌药物。TRAIL还可以与TRAIL-R4等非功能受体结合，但其抑制TRAIL诱导的细胞凋亡的可能性仍存在争议。我们在这里表明，TRAIL-R4，无论是内源性的还是异位表达的，都能抑制TRAIL诱导的细胞凋亡。有趣的是，化疗药物与TRAIL的结合可恢复TRAIL-R4表达细胞中肿瘤细胞对凋亡的敏感性。这种敏化主要发生在死亡诱导信号复合体(DISC)水平，通过增强caspase-8的招募和激活，受到c-flip表达的影响，并且不依赖于线粒体。重要的是，TRAIL-R4的表达阻止了TRAIL诱导的裸鼠肿瘤消退，但TRAIL诱导的肿瘤消退可以通过化疗恢复。我们的结果清楚地支持TRAIL-R4在控制TRAIL信号转导中的负调控功能，并揭示了TRAIL-R4与c-FLIP协同抑制TRAIL诱导的细胞死亡的能力。《细胞死亡与分化》(2011年)18700711；doi：10.1038/cdd.2010.144；2010年11月12日在线发布
TNF-related apoptosis-inducing ligand or Apo2L (Apo2L/TRAIL) is a promising anti-cancer drug owing to its ability to trigger apoptosis by binding to TRAIL-R1 or TRAIL-R2, two membrane-bound receptors that are often expressed by tumor cells. TRAIL can also bind non-functional receptors such as TRAIL-R4, but controversies still exist regarding their potential to inhibit TRAIL-induced apoptosis. We show here that TRAIL-R4, expressed either endogenously or ectopically, inhibits TRAIL-induced apoptosis. Interestingly, the combination of chemotherapeutic drugs with TRAIL restores tumor cell sensitivity to apoptosis in TRAIL-R4-expressing cells. This sensitization, which mainly occurs at the death-inducing signaling complex (DISC) level, through enhanced caspase-8 recruitment and activation, is compromised by c-FLIP expression and is independent of the mitochondria. Importantly, TRAIL-R4 expression prevents TRAIL-induced tumor regression in nude mice, but tumor regression induced by TRAIL can be restored with chemotherapy. Our results clearly support a negative regulatory function for TRAIL-R4 in controlling TRAIL signaling, and unveil the ability of TRAIL-R4 to cooperate with c-FLIP to inhibit TRAIL-induced cell death. Cell Death and Differentiation (2011) 18, 700-711; doi:10.1038/cdd.2010.144; published online 12 November 2010