Li Yuan, Lu Lu, Zhang Guangtao, Ji Guang, Xu Hanchen
Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine Shanghai 200032, China.
Am J Cancer Res. 2022 May 15;12(5):2277-2292. eCollection 2022.
Endoplasmic reticulum (ER) stress occurs when proteins are affected by various factors, fail to fold properly into higher structures and accumulate in the lumen of the ER, which activates the unfolded protein response (UPR) to restore normal cellular function or induce apoptosis as a self-protective mechanism. However, a growing number of studies have shown that the three branches of ER stress and the UPR can mediate inflammation and cancer development by interacting with inflammatory transformation-related signaling pathways. Targeting the UPR, especially the use of small molecules that target the active sites of the enzymes IRE1α and PERK and BIP/GRP78 inhibitors are potential strategies for treating tumors and have shown promising results in some tumor models. Therefore, in this review, we summarize the progress of ER stress/UPR research and the signaling pathways associated with inflammatory cancer transformation, provide an in-depth description of the mechanisms of these pathways, and outline strategies in the field of UPR biology in tumor therapy to provide new ideas for the mechanisms of inflammatory cancer transformation and tumor-related treatment.
当蛋白质受到各种因素影响,无法正确折叠成更高结构并在内质网(ER)腔中积累时,就会发生内质网应激,这会激活未折叠蛋白反应(UPR)以恢复正常细胞功能或诱导细胞凋亡作为一种自我保护机制。然而,越来越多的研究表明,内质网应激和未折叠蛋白反应的三个分支可通过与炎症转化相关信号通路相互作用来介导炎症和癌症发展。靶向未折叠蛋白反应,特别是使用靶向酶IRE1α和PERK活性位点的小分子以及BIP/GRP78抑制剂,是治疗肿瘤的潜在策略,并且在一些肿瘤模型中已显示出有前景的结果。因此,在本综述中,我们总结了内质网应激/未折叠蛋白反应研究的进展以及与炎症性癌症转化相关的信号通路,深入描述了这些通路的机制,并概述了未折叠蛋白反应生物学领域在肿瘤治疗中的策略,为炎症性癌症转化机制和肿瘤相关治疗提供新思路。