High-order TRAIL oligomer formation in TRAIL-coated lipid nanoparticles enhances DR5 cross-linking and increases antitumour effect against colon cancer
High-order TRAIL oligomer formation in TRAIL-coated lipid nanoparticles enhances DR5 cross-linking and increases antitumour effect against colon cancer
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DOI：
10.1016/j.canlet.2016.10.005
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发表时间：
2016-12-28
期刊：
影响因子：
9.7
通讯作者：
Martinez-Lostao, Luis
中科院分区：
文献类型：
--
作者：
De Miguel, Diego;Gallego-Lleyda, Ana;Martinez-Lostao, Luis
在过去的几年里，人们投入了大量的精力来开发具有更高生物活性的新的TRAIL制剂，试图克服许多原发肿瘤对传统的可溶性TRAIL(STRAIL)的耐药性。在我们的团队中，我们已经产生了用sTRAIL装饰的人造脂质纳米颗粒(LW-TRAIL)，模拟含有TRAIL的生理外体，T细胞激活后通过它释放TRAIL。我们已经证明，与临床试验中使用的一种形式的sTRAIL相比，LUV-TRAIL对耐药的血液肿瘤细胞和上皮性癌细胞具有更强的细胞毒性。在这项研究中，我们测试了LW-TRAIL在几种对sTRAIL不同敏感性的人结肠癌细胞系中的表达。LW-TRAIL显著提高了所测试的所有结肠癌细胞系中sTRAIL的细胞毒性。为了弄清LUV-TRAIL提高细胞毒性的分子机制，我们证明了TRAIL包裹的脂质纳米粒能够比sTRAIL更有效地激活DR5，这依赖于LW-TRAIL促进DRS在细胞表面聚集的能力。此外，我们发现TRAIL分子只在LW-TRAIL中以高阶低聚物的形式排列，这可能是它们增强DR5聚集能力的原因。最后，在裸鼠HCT-116移植瘤的体内模型中，LW-TRAIL的抗肿瘤活性明显优于sTRAIL，验证了其潜在的临床应用。(C)2016爱思唯尔爱尔兰有限公司。保留所有权利。
During the last years, a great effort has been invested into developing new TRAIL formulations with increased bioactivity, trying to overcome the resistance to conventional soluble TRAIL (sTRAIL) exhibited by many primary tumours. In our group, we have generated artificial lipid nanoparticles decorated with sTRAIL (LW-TRAIL), emulating the physiological TRAIL-containing exosomes by which T-cells release TRAIL upon activation. We already demonstrated that LUV-TRAIL has greater cytotoxicity against both chemoresistant haematologic tumour cells and epithelial carcinoma cells compared to a form of sTRAIL similar to that used in clinical trials. In this study we have tested LW-TRAIL in several human colon cancer cell lines with different sensitivity to sTRAIL. LW-TRAIL significantly improved sTRAIL cytotoxicity in all colon cancer cell lines tested. Trying to ascertain the molecular mechanism by which LUV-TRAIL exhibited improved cytotoxicity, we demonstrated that TRAIL-coated lipid nanoparticles were able to activate DR5 more efficiently than sTRAIL, and this relied on LW-TRAIL ability to promote DRS clustering on the cell surface. Moreover, we show that TRAIL molecules are arranged in higher order oligomers only in LW-TRAIL, which may explain their enhanced DR5 clustering ability. Finally, LW-TRAIL showed significantly better antitumour activity than sTRAIL in an in vivo model using HCT-116 xenograft tumours in nude mice, validating its potential clinical application. (C) 2016 Elsevier Ireland Ltd. All rights reserved.