Klin Onkol. 2023 Winter;36(6):440-446. doi: 10.48095/ccko2023440.
The endoplasmic reticulum (ER), an organelle composed of a system of cisternae and tubules, is essential for many cellular processes, including protein synthesis and transport. When misfolded proteins accumulate in the ER lumen, ER stress is induced, and the subsequent response to the disruption of homeostasis is the activation of the unfolded protein response (UPR). The purpose of this process is to restore homeostasis by increasing the capacity of the ER and its ability to fold proteins. Activation of the homeostatic UPR occurs via one of three transmembrane proteins, inositol-requiring enzyme 1a (IRE1a), protein kinase R-like ER kinase (PERK) and activating transcription factor 6 (ATF6). Failure of the attempt to restore homeostasis, on the other hand, leads to the development of terminal UPR and apoptosis via hyperactivation of the same proteins. Activation of UPR has been described in many malignancies, including multiple myeloma (MM), which is characterized by malignant transformation of plasma cells and increased monoclonal immunoglobulin synthesis, where the role of the ER is of particular importance. Despite advances in the treatment of MM, the disease remains difficult to treat and targeting signaling pathways associated with the UPR could, for example, enhance the effect of proteasome inhibitors.
This review intends to present the molecular response to ER stress under physiological circumstances and in the context of cancer, particularly with regard to potential therapeutic targets in MM.
内质网（ER）是一种由一系列潴泡和小管组成的细胞器，对于许多细胞过程至关重要，包括蛋白质合成和运输。当错误折叠的蛋白质在内质网腔中积累时，会引发内质网应激，随后对平衡破坏的反应是激活未折叠蛋白反应（UPR）。这个过程的目的是通过增加内质网的容量和折叠蛋白质的能力来恢复平衡。稳态 UPR 的激活是通过三种跨膜蛋白之一实现的，即肌醇需求酶 1a（IRE1a）、蛋白激酶 R 样内质网激酶（PERK）和激活转录因子 6（ATF6）。另一方面，当试图恢复平衡失败时，同样的蛋白质会过度激活，导致终末 UPR 和细胞凋亡的发展。UPR 的激活已在许多恶性肿瘤中被描述，包括多发性骨髓瘤（MM），其特征是浆细胞的恶性转化和单克隆免疫球蛋白合成增加，内质网的作用尤为重要。尽管 MM 的治疗取得了进展，但该疾病仍然难以治疗，针对与 UPR 相关的信号通路的治疗方法，例如蛋白酶体抑制剂，可能会增强其效果。
本综述旨在介绍生理情况下和癌症背景下内质网应激的分子反应，特别是在多发性骨髓瘤中的潜在治疗靶点。
