Inositol requiring enzyme 1 alpha (IRE1α) is one of three signaling sensors in the unfolding protein response (UPR) that alleviates endoplasmic reticulum (ER) stress in cells and functions to promote cell survival. During conditions of irrevocable stress, proapoptotic gene expression is induced to promote cell death. One of the three signaling stressors, IRE1α is an serine/threonine-protein kinase/endoribonuclease (RNase) that promotes nonconventional splicing of XBP1 mRNA that is translated to spliced XBP1 (XBP1s), an active prosurvival transcription factor. Interestingly, elevated IRE1α and XBP1s are both associated with poor cancer survival and drug resistance. In this study, we used next-generation sequencing analyses to demonstrate that triazoloacridone C-1305, a microtubule stabilizing agent that also has topoisomerase II inhibitory activity, dramatically decreases XBP1s mRNA levels and protein production during ER stress conditions, suggesting that C-1305 does this by decreasing IRE1α’s endonuclease activity.

中文翻译：

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三唑并吖啶酮 C-1305 通过作为潜在的 IRE1α 内切核糖核酸酶抑制剂来损害 XBP1 剪接

肌醇需要酶 1 α (IRE1α) 是未折叠蛋白反应 (UPR) 中的三个信号传感器之一，可减轻细胞中的内质网 (ER) 应激，并具有促进细胞存活的功能。在不可逆转的压力条件下，促凋亡基因表达被诱导以促进细胞死亡。作为三个信号压力源之一，IRE1α 是一种丝氨酸/苏氨酸蛋白激酶/核糖核酸内切酶 (RNase)，可促进 XBP1 mRNA 的非常规剪接，该剪接被翻译为剪接的 XBP1 (XBP1s)，这是一种活性促存活转录因子。有趣的是，升高的 IRE1α 和 XBP1 都与较差的癌症存活率和耐药性有关。在这项研究中，我们使用新一代测序分析来证明三唑并吖啶酮 C-1305，一种微管稳定剂，也具有拓扑异构酶 II 抑制活性，