Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Hypothalamic Pituitary Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China.
CNS Neurosci Ther. 2024 Jul;30(7):e14839. doi: 10.1111/cns.14839.
The role of the unfolded protein response (UPR) has been progressively unveiled over the last decade and several studies have investigated its implication in glioblastoma (GB) development. The UPR restores cellular homeostasis by triggering the folding and clearance of accumulated misfolded proteins in the ER consecutive to endoplasmic reticulum stress. In case it is overwhelmed, it induces apoptotic cell death. Thus, holding a critical role in cell fate decisions.
This article, reviews how the UPR is implicated in cell homeostasis maintenance, then surveils the evidence supporting the UPR involvement in GB genesis, progression, angiogenesis, GB stem cell biology, tumor microenvironment modulation, extracellular matrix remodeling, cell fate decision, invasiveness, and grading. Next, it concurs the evidence showing how the UPR mediates GB chemoresistance-related mechanisms.
The UPR stress sensors IRE1, PERK, and ATF6 with their regulator GRP78 are upregulated in GB compared to lower grade gliomas and normal brain tissue. They are activated in response to oncogenes and are implicated at different stages of GB progression, from its genesis to chemoresistance and relapse. The UPR arms can be effectors of apoptosis as mediators or targets.
Recent research has established the role of the UPR in GB pathophysiology and chemoresistance. Targeting its different sensors have shown promising in overcoming GB chomo- and radioresistance and inducing apoptosis.
未折叠蛋白反应 (UPR) 的作用在过去十年中逐渐被揭示，并且已经有几项研究调查了其在神经胶质瘤 (GB) 发展中的作用。UPR 通过触发内质网应激后内质网中积累的错误折叠蛋白的折叠和清除来恢复细胞内稳态。如果它不堪重负，它会诱导细胞凋亡。因此，它在细胞命运决策中起着关键作用。
本文综述了 UPR 如何参与细胞内稳态的维持，然后综述了支持 UPR 参与 GB 发生、进展、血管生成、GB 干细胞生物学、肿瘤微环境调节、细胞外基质重塑、细胞命运决定、侵袭性和分级的证据。接下来，它一致表明 UPR 如何介导与 GB 化学抗性相关的机制的证据。
与低级别神经胶质瘤和正常脑组织相比，UPR 的应激传感器 IRE1、PERK 和 ATF6 及其调节蛋白 GRP78 在 GB 中上调。它们在致癌基因的作用下被激活，并在从发生到化学抗性和复发的不同阶段参与 GB 的进展。UPR 臂可以作为介质或靶标成为细胞凋亡的效应物。
最近的研究已经确立了 UPR 在 GB 病理生理学和化学抗性中的作用。靶向其不同的传感器已显示出在克服 GB 化学和放射抗性并诱导细胞凋亡方面的潜力。
