内质网应激/未折叠蛋白反应在抑制脑胶质母细胞瘤中的研究进展

Research advances in endoplasmic reticulum stress/unfolded protein reaction in inhibiting glioblastoma

摘要:

胶质母细胞瘤（GBM）是一种预后极差的中枢神经系统恶性肿瘤，具有手术难以切除、高侵袭性、增生性及强耐药性等特点。内质网（ER）应激会破坏细胞中的其他蛋白质稳态，从而导致未折叠的蛋白质响应（UPR）激活，这对于恢复这种平衡和细胞存活至关重要。除了作为一种适应性反应外，最近UPR还与肿瘤发生有关。肿瘤微环境中普遍存在的缺氧、活性氧和营养物质剥夺是众所周知的UPR诱因。在这里，笔者回顾目前对成人最具生命威胁的GBM中UPR的认识。患者样品显示出UPR的慢性激活，体外标准化学疗法和放射疗法通过加重ER应激导致细胞死亡而部分起作用。UPR与凋亡诱导剂如TRAIL和MDA-7的敏感性增强有关。最后，内质网应激被认为与GBM干细胞内稳态的维持有关。UPR中的IRE1与PERK传感器在原位GBM小鼠模型中的作用均有报道，但直接作用仍有待证明。综上所述，UPR似乎可通过抑制其活性成为GBM新的干预手段中一个有希望的治疗靶点。

Abstract:

Glioblastoma is a malignant tumor of the central nervous system with poor prognosis and has the features of difficult surgical resection， high invasiveness and proliferation， and strong drug resistance. Endoplasmic reticulum stress （ERS） disrupts the homeostasis of other proteins in cells and thus leads to the activation of unfolded protein response （UPR）， which is essential to the restoration of this balance and cell survival. Except as an adaptive response， UPR is also associated with tumorigenesis. Hypoxia， reactive oxygen species， and deprivation of nutrients in tumor microenvironment are the well-known predisposing factors for UPR. This article reviews the current understanding of UPR in adults with the most life-threatening disease glioblastoma multiforme （GBM）. Chronic activation of UPR is observed in the samples of patients， and standard chemotherapy and radiotherapy can lead to cell death partially by aggravating ERS. UPR is associated with increased sensitivity of apoptosis inducers such as TRAIL and MDA-7. Finally， ERS is considered associated with the maintenance of homeostasis in GBM stem cells. The role of IRE1 and PERK sensors in UPR in the mouse model of GBM has been reported， while further studies are still needed to investigate their direct roles. In summary， UPR may become a promising target for new therapeutic interventions for GBM by inhibiting its activity.