Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece.
Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece.
Pharmacol Res. 2020 Jul;157:104823. doi: 10.1016/j.phrs.2020.104823. Epub 2020 Apr 17.
Gliomas remain a group of malignant brain tumors with dismal prognosis and limited treatment options with molecular mechanisms being constantly investigated. The past decade, extracellular stress and intracellular DNA damage have been shown to disturb proteostasis leading to Endoplasmic Reticulum (ER) stress that is implicated in the regulation of gene expression and the pathogenesis of several tumor types, including gliomas. Upon ER stress induction, neoplastic cells activate the adaptive mechanism of unfolded protein response (UPR), an integrated signaling system that either restores ER homeostasis or induces cell apoptosis. Recently, the manipulation of the UPR has emerged as a new therapeutic target in glioma treatment. General UPR activators or selective GRP78, ATF6 and PERK inducers have been detected to modulate cell proliferation and induce apoptosis of glioma cells. At the same time, target-specific UPR inhibitors and small molecule proteostasis disruptors, work in reverse to increase misfolded proteins and cause a dysregulation in protein maturation and sorting, thus preventing the growth of neoplastic cells. Herein, we discuss the pathogenic implication of ER stress in gliomas onset and progression, providing an update on the current UPR modifying agents that can be potentially used in glioma treatment.
神经胶质瘤仍然是一组恶性脑肿瘤，预后不良，治疗选择有限，其分子机制仍在不断研究中。过去十年，细胞外应激和细胞内 DNA 损伤已被证明会破坏蛋白质稳态，导致内质网 (ER) 应激，这与几种肿瘤类型（包括神经胶质瘤）的基因表达调控和发病机制有关。在 ER 应激诱导下，肿瘤细胞激活未折叠蛋白反应 (UPR) 的适应性机制，这是一种整合的信号系统，可恢复 ER 稳态或诱导细胞凋亡。最近，UPR 的调控已成为神经胶质瘤治疗的新治疗靶点。已检测到通用 UPR 激活剂或选择性 GRP78、ATF6 和 PERK 诱导剂来调节细胞增殖并诱导神经胶质瘤细胞凋亡。与此同时，针对特定靶点的 UPR 抑制剂和小分子蛋白质稳态破坏剂则相反，它们会增加错误折叠的蛋白质，并导致蛋白质成熟和分类失调，从而阻止肿瘤细胞的生长。在此，我们讨论了 ER 应激在神经胶质瘤发病和进展中的发病意义，并提供了关于当前 UPR 修饰剂的最新信息，这些修饰剂可能用于神经胶质瘤的治疗。
