SNIPER(TACC3) induces cytoplasmic vacuolization and sensitizes cancer cells to Bortezomib.
SNIPER(TACC3) induces cytoplasmic vacuolization and sensitizes cancer cells to Bortezomib.
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DOI：
10.1111/cas.13198
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发表时间：
2017-05
期刊：
影响因子：
5.7
通讯作者：
Naito M
中科院分区：
文献类型：
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作者：
Ohoka N;Nagai K;Shibata N;Hattori T;Nara H;Cho N;Naito M
我们之前开发了一种针对转化酸性卷曲螺旋-3（TACC 3）的杂合小分子SNIPER（特异性和非遗传性IAP依赖性蛋白质擦除器），SNIPER（TACC 3），其诱导TACC 3蛋白的蛋白酶体降解。在这项研究中，我们发现SNIPER（TACC 3）在癌细胞中选择性地诱导来自内质网（ER）的细胞质空泡化和凋亡样细胞死亡。机制分析表明，需要X连锁凋亡抑制蛋白（XIAP）的泛素化蛋白聚集体的积累诱导ER应激，这导致涉及X盒结合蛋白-1（XBP-1）的ER应激反应和癌细胞中ER衍生的空泡化。重要的是，蛋白酶体的抑制增强了SNIPER（TACC 3）诱导的空泡化，SNIPER（TACC 3）和硼替佐米的联合治疗在几种癌细胞系中表现出协同抗癌活性。通过SNIPER（TACC 3）诱导癌细胞中的凋亡样细胞死亡可用于治疗通过XIAP的过表达而耐受细胞凋亡的癌细胞。
We previously developed a hybrid small molecule SNIPER (Specific and Nongenetic IAP‐dependent Protein ERaser) against transforming acidic coiled‐coil‐3 (TACC3), SNIPER(TACC3), that induces proteasomal degradation of TACC3 protein. In this study, we found that SNIPER(TACC3) induces cytoplasmic vacuolization derived from endoplasmic reticulum (ER) and paraptosis‐like cell death selectively in cancer cells. Mechanistic analysis suggests that accumulation of ubiquitylated protein aggregates that requires X‐linked inhibitor of apoptosis protein (XIAP) induces ER stress, which results in ER‐stress responses involving X‐box binding protein‐1 (XBP‐1) and ER‐derived vacuolization in cancer cells. Importantly, inhibition of proteasome enhanced the SNIPER(TACC3)‐induced vacuolization, and the combination treatment of SNIPER(TACC3) and bortezomib exhibited a synergistic anticancer activity in several cancer cell lines. The induction of paraptosis‐like cell death in cancer cells by SNIPER(TACC3) could be applied to treat cancer cells resistant to undergo apoptosis by overexpression of XIAP.