Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
FASEB J. 2011 Apr;25(4):1353-8. doi: 10.1096/fj.10-170480. Epub 2010 Dec 27.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily. TRAIL is promising for anticancer therapy because it induces apoptosis in cancer cells with little or no toxicity to normal cells; hence, TRAIL-receptor agonists are currently undergoing clinical trials for cancer treatment. However, many molecular signaling mechanisms in TRAIL signaling are not completely characterized. The functions of adaptor proteins, including TNF-receptor-associated death domain protein (TRADD) and receptor-interacting protein-1 (RIP1) in TRAIL signaling have been controversial. We demonstrate that while wild-type mouse embryonic fibroblasts (MEFs) are completely resistant to TRAIL-induced apoptosis, MEFs derived from Tradd(-/-) mice are hypersensitive to TRAIL (IC(50)~0.5 nM rmTRAIL, 24 h), an effect also seen in primary keratinocytes treated with TRAIL/CHX. Restoration of TRADD in Tradd(-/-) MEFs restores TRAIL resistance, indicating that TRADD plays a survival role in TRAIL signaling. We show that TRADD is recruited to the TRAIL-receptor complex, and RIP1 recruitment is mediated by TRADD. While early activation of the MAP kinase ERK is deficient in Tradd(-/-) cells, the main mechanism for enhanced TRAIL sensitivity is likely due to increased recruitment of FADD to the receptor complex, indicating that TRADD may limit FADD binding within the receptor complex and also mediate RIP1-dependent nonapoptotic signaling events, thus reducing caspase activation and subsequent apoptosis. These novel findings have potential implications for cancer therapy using TRAIL-receptor agonists.
肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）是 TNF 超家族的一员。TRAIL 在抗癌治疗中有很大的应用前景，因为它能诱导癌细胞凋亡，而对正常细胞的毒性很小或没有；因此，TRAIL 受体激动剂目前正在进行癌症治疗的临床试验。然而，TRAIL 信号转导中的许多分子信号机制尚未完全阐明。衔接蛋白的功能，包括 TNF 受体相关死亡结构域蛋白（TRADD）和受体相互作用蛋白-1（RIP1）在 TRAIL 信号转导中的作用一直存在争议。我们证明，虽然野生型小鼠胚胎成纤维细胞（MEFs）对 TRAIL 诱导的凋亡完全有抗性，但来自 Tradd(-/-) 小鼠的 MEFs 对 TRAIL 非常敏感（IC(50)~0.5 nM rmTRAIL，24 h），用 TRAIL/CHX 处理的原代角质形成细胞也会出现这种现象。在 Tradd(-/-) MEFs 中恢复 TRADD 可恢复 TRAIL 抗性，表明 TRADD 在 TRAIL 信号转导中起生存作用。我们表明，TRADD 被募集到 TRAIL 受体复合物中，并且 RIP1 的募集是由 TRADD 介导的。虽然在 Tradd(-/-) 细胞中早期激活 MAP 激酶 ERK 是缺陷的，但增强 TRAIL 敏感性的主要机制可能是由于 FADD 向受体复合物的募集增加，表明 TRADD 可能限制受体复合物内的 FADD 结合，并介导 RIP1 依赖性非凋亡信号事件，从而减少 caspase 激活和随后的细胞凋亡。这些新发现对使用 TRAIL 受体激动剂的癌症治疗具有潜在的意义。
