PDF(Pubmed)
Abstract：
The endoplasmic reticulum maintains proteostasis, which can be disrupted by oxidative stress, nutrient deprivation, hypoxia, lack of ATP, and toxicity caused by xenobiotic compounds, all of which can result in the accumulation of misfolded proteins. These stressors activate the unfolded protein response (UPR), which aims to restore proteostasis and avoid cell death. However, endoplasmic response-associated degradation (ERAD) is sometimes triggered to degrade the misfolded and unassembled proteins instead. If stress persists, cells activate three sensors: PERK, IRE-1, and ATF6. Glioma cells can use these sensors to remain unresponsive to chemotherapeutic treatments. In such cases, the activation of ATF4 via PERK and some proteins via IRE-1 can promote several types of cell death. The search for new antitumor compounds that can successfully and directly induce an endoplasmic reticulum stress response ranges from ligands to oxygen-dependent metabolic pathways in the cell capable of activating cell death pathways. Herein, we discuss the importance of the ER stress mechanism in glioma and likely therapeutic targets within the UPR pathway, as well as chemicals, pharmaceutical compounds, and natural derivatives of potential use against gliomas.
摘要：
内质网维持蛋白质稳定，可以被氧化应激破坏，营养剥夺，缺氧,缺乏ATP,和由异生化合物引起的毒性，所有这些都会导致错误折叠蛋白质的积累。这些应激源激活未折叠的蛋白质反应（UPR），其目的是恢复蛋白质稳定和避免细胞死亡。然而,内质反应相关降解（ERAD）有时会触发降解错误折叠和未组装的蛋白质。如果压力持续存在，细胞激活三个传感器:PERK,IRE-1和ATF6。神经胶质瘤细胞可以使用这些传感器来保持对化疗治疗无反应。在这种情况下,通过PERK激活ATF4和通过IRE-1激活一些蛋白质可以促进几种类型的细胞死亡。寻找可以成功且直接诱导内质网应激反应的新的抗肿瘤化合物的范围从配体到能够激活细胞死亡途径的细胞中的氧依赖性代谢途径。在这里，我们讨论了神经胶质瘤中ER应激机制的重要性以及UPR通路中可能的治疗靶点，以及化学品，药物化合物，和天然衍生物的潜在用途的神经胶质瘤。
