Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing.
Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing.
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DOI：
10.1038/bcj.2012.26
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发表时间：
2012-07
影响因子：
12.8
通讯作者：
Iida, S.
中科院分区：
文献类型：
--
作者：
Ri, M.;Tashiro, E.;Oikawa, D.;Shinjo, S.;Tokuda, M.;Yokouchi, Y.;Narita, T.;Masaki, A.;Ito, A.;Ding, J.;Kusumoto, S.;Ishida, T.;Komatsu, H.;Shiotsu, Y.;Ueda, R.;Iwawaki, T.;Imoto, M.;Iida, S.
IRE 1 α-XBP 1通路是内质网（ER）应激反应的关键组成部分，被认为是多发性骨髓瘤（MM）细胞存活的关键调节因子。因此，针对这一途径的小分子抑制剂的可用性将为MM提供一种新的化疗策略。在这里，我们筛选了ER应激诱导的XBP 1激活的小分子抑制剂，并从放线菌菌株的培养液中鉴定了丰卡霉素。Toyocamycin被证明可以抑制毒胡萝卜素，衣霉素和2-脱氧葡萄糖诱导的HeLa细胞中的XBP 1 mRNA剪接，而不影响激活转录因子6（ATF 6）和PKR样ER激酶（PERK）的激活。此外，虽然丰卡霉素不能抑制IRE 1 α磷酸化，但它在体外阻止IRE 1 α诱导的XBP 1 mRNA切割。因此，丰卡霉素是IRE 1 α诱导的XBP 1 mRNA切割的抑制剂。丰霉素不仅抑制ER应激诱导的，而且抑制MM细胞系以及患者原始样本中XBP 1表达的组成性激活。它显示出与硼替佐米的协同作用，并以剂量依赖性方式在纳摩尔水平诱导MM细胞（包括硼替佐米耐药细胞）凋亡。它还抑制了异种移植物在人MM的体内模型中的生长。总之，我们的研究结果表明丰卡霉素作为开发抗MM治疗的先导化合物，而XBP 1作为抗MM治疗的适当分子靶点。
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.
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影响因子：
64.8
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Reimold, AM;Iwakoshi, NN;Glimcher, LH
通讯作者：
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