Department of Inorganic Chemistry, Medical University of Gdansk, Hallera 107, 80-416, Gdańsk, Poland.
Department of Biology and Pharmaceutical Botany, Medical University of Gdansk, Hallera 107, 80-416, Gdańsk, Poland.
Cell Mol Biol Lett. 2021 Mar 17;26(1):11. doi: 10.1186/s11658-021-00255-y.
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.
肌醇需求酶 1 阿尔法（IRE1α）是未折叠蛋白反应（UPR）中的三种信号传感器之一，可减轻细胞内质网（ER）应激，并发挥促进细胞存活的作用。在不可逆转的应激条件下，促凋亡基因表达被诱导以促进细胞死亡。IRE1α 是三种信号应激源之一，是丝氨酸/苏氨酸蛋白激酶/内切核糖核酸酶（RNase），可促进 XBP1 mRNA 的非常规剪接，该剪接体被翻译为剪接 XBP1（XBP1s），这是一种活跃的抗凋亡转录因子。有趣的是，IRE1α 和 XBP1s 的升高均与癌症预后不良和耐药性相关。在这项研究中，我们使用下一代测序分析表明，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，在 ER 应激条件下显著降低 XBP1s mRNA 水平和蛋白产生，表明 C-1305 通过降低 IRE1α 的内切核酸酶活性来实现这一点。
