USP11-dependent selective cIAP2 deubiquitylation and stabilization determine sensitivity to Smac mimetics
USP11-dependent selective cIAP2 deubiquitylation and stabilization determine sensitivity to Smac mimetics
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DOI：
10.1038/cdd.2014.234
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发表时间：
2015-09-01
影响因子：
12.4
通讯作者：
Song, J.
中科院分区：
文献类型：
--
作者：
Lee, E-W;Seong, D.;Song, J.
鉴于其在细胞凋亡抑制中的重要作用，细胞凋亡抑制蛋白（IAPs）最近成为癌症治疗的一个有吸引力的靶点。在这里，我们报道了细胞IAP2 （cIAP2）在几种癌细胞系中特异性稳定，导致对Smac模拟物（如BV6和biinapant）产生抗性。特别是，我们的研究结果表明，cIAP2缺失，而不是cIAP1缺失，使癌细胞对Smac模拟物诱导的凋亡敏感。泛素特异性蛋白酶11 （USP11）是直接稳定cIAP2的去泛素化酶。USP11过表达常见于结直肠癌和黑色素瘤，并与较差的生存率相关。在我们的研究中，表达高水平USP11的癌细胞对Smac模拟物诱导的cIAP2降解表现出很强的抗性。此外，在异种移植模型中，USP11下调使这些细胞对TRAIL和BV6诱导的凋亡敏感，并抑制肿瘤生长。最后，TNF α /JNK通路诱导USP11表达并维持cIAP2的稳定性，提示另一种TNF α依赖的细胞存活通路。总的来说，我们的数据表明，usp11稳定的cIAP2可能成为针对iap的临床方法的障碍。
Given their crucial role in apoptosis suppression, inhibitor of apoptosis proteins (IAPs) have recently become attractive targets for cancer therapy. Here, we report that cellular IAP2 (cIAP2) is specifically stabilized in several cancer cell lines, leading to resistance to Smac mimetics, such as BV6 and birinapant. In particular, our results showed that cIAP2 depletion, but not cIAP1 depletion, sensitized cancer cells to Smac mimetic-induced apoptosis. Ubiquitin-specific protease 11 (USP11) is a deubiquitylase that directly stabilizes cIAP2. USP11 overexpression is frequently found in colorectal cancer and melanoma and is correlated with poor survival. In our study, cancer cell lines expressing high levels of USP11 exhibited strong resistance to Smac mimetic-induced cIAP2 degradation. Furthermore, USP11 downregulation sensitized these cells to apoptosis induced by TRAIL and BV6 and suppressed tumor growth in a xenograft model. Finally, the TNF alpha/JNK pathway induced USP11 expression and maintained cIAP2 stability, suggesting an alternative TNF alpha-dependent cell survival pathway. Collectively, our data suggest that USP11-stabilized cIAP2 may serve as a barrier against IAP-targeted clinical approaches.