未折叠蛋白反应
癌症研究
干细胞
细胞培养
信号转导
生物
细胞生长
下调和上调
细胞凋亡
医学
细胞生物学
遗传学
基因
作者
Guanzheng Liu,Jiefeng Yu,Runqiu Wu,Lin Shi,Xu Zhang,Wanhong Zhang,Xiaorong Zhong,Yifeng Wang,Huan Li,Yang Shen,Changyong Wu,Rutong Yu,Mingshan Niu,Xuejiao Liu
标识
DOI:10.1038/s41419-021-04023-w
摘要
Abstract Glioblastoma multiforme (GBM) is an extremely aggressive brain tumor for which new therapeutic approaches are urgently required. Unfolded protein response (UPR) plays an important role in the progression of GBM and is a promising target for developing novel therapeutic interventions. We identified ubiquitin-activating enzyme 1 (UBA1) inhibitor TAK-243 that can strongly induce UPR in GBM cells. In this study, we evaluated the functional activity and mechanism of TAK-243 in preclinical models of GBM. TAK-243 significantly inhibited the survival, proliferation, and colony formation of GBM cell lines and primary GBM cells. It also revealed a significant anti-tumor effect on a GBM PDX animal model and prolonged the survival time of tumor-bearing mice. Notably, TAK-243 more effectively inhibited the survival and self-renewal ability of glioblastoma stem cells (GSCs) than GBM cells. Importantly, we found that the expression level of GRP78 is a key factor in determining the sensitivity of differentiated GBM cells or GSCs to TAK-243. Mechanistically, UBA1 inhibition disrupts global protein ubiquitination in GBM cells, thereby inducing ER stress and UPR. UPR activates the PERK/ATF4 and IRE1α/XBP signaling axes. These findings indicate that UBA1 inhibition could be an attractive strategy that may be potentially used in the treatment of patients with GBM, and GRP78 can be used as a molecular marker for personalized treatment by targeting UBA1.
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