文章：

多发性骨髓瘤细胞毒性药物Toyocamycin作为内质网应激诱导的XBP1 mRNA剪接的有效抑制剂的鉴定

Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing

原文发布日期：2012-07-20

DOI: 10.1038/bcj.2012.26

类型: Original Article

开放获取: 是

英文摘要：

The IRE1α-XBP1 pathway, a key component of the endoplasmic reticulum (ER) stress response, is considered to be a critical regulator for survival of multiple myeloma (MM) cells. Therefore, the availability of small-molecule inhibitors targeting this pathway would offer a new chemotherapeutic strategy for MM. Here, we screened small-molecule inhibitors of ER stress-induced XBP1 activation, and identified toyocamycin from a culture broth of an Actinomycete strain. Toyocamycin was shown to suppress thapsigargin-, tunicamycin- and 2-deoxyglucose-induced XBP1 mRNA splicing in HeLa cells without affecting activating transcription factor 6 (ATF6) and PKR-like ER kinase (PERK) activation. Furthermore, although toyocamycin was unable to inhibit IRE1α phosphorylation, it prevented IRE1α-induced XBP1 mRNA cleavage in vitro. Thus, toyocamycin is an inhibitor of IRE1α-induced XBP1 mRNA cleavage. Toyocamycin inhibited not only ER stress-induced but also constitutive activation of XBP1 expression in MM lines as well as primary samples from patients. It showed synergistic effects with bortezomib, and induced apoptosis of MM cells including bortezomib-resistant cells at nanomolar levels in a dose-dependent manner. It also inhibited growth of xenografts in an in vivo model of human MM. Taken together, our results suggest toyocamycin as a lead compound for developing anti-MM therapy and XBP1 as an appropriate molecular target for anti-MM therapy.

摘要翻译： 

IRE1α-XBP1通路作为内质网应激反应的关键组成部分，被认为是多发性骨髓瘤细胞存活的重要调节因子。因此，针对该通路的小分子抑制剂的研发将为多发性骨髓瘤提供新的化疗策略。本研究通过筛选内质网应激诱导的XBP1活化小分子抑制剂，从放线菌菌株培养液中鉴定出丰加霉素。实验表明，丰加霉素可抑制HeLa细胞中毒胡萝卜素、衣霉素和2-脱氧葡萄糖诱导的XBP1 mRNA剪接，且不影响转录激活因子6（ATF6）和PKR样内质网激酶（PERK）的活化。尽管丰加霉素不能抑制IRE1α磷酸化，但在体外实验中它能阻止IRE1α介导的XBP1 mRNA切割，因此被确定为IRE1α诱导的XBP1 mRNA切割抑制剂。丰加霉素不仅能抑制多发性骨髓瘤细胞系中内质网应激诱导的XBP1表达，还能抑制其组成性活化，对原代患者样本同样有效。该药物与硼替佐米具有协同作用，能以纳摩尔浓度剂量依赖性方式诱导硼替佐米耐药细胞在内的多发性骨髓瘤细胞凋亡。在人体多发性骨髓瘤体内模型中，丰加霉素还可抑制异种移植瘤的生长。综上所述，我们的研究结果表明丰加霉素可作为抗多发性骨髓瘤疗法的先导化合物，且XBP1是抗多发性骨髓瘤治疗的合适分子靶点。

原文链接：

Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing