替莫唑胺
自噬
PARP1
癌症研究
体内
流出
生物
化学
细胞生物学
胶质瘤
聚ADP核糖聚合酶
生物化学
细胞凋亡
遗传学
聚合酶
基因
作者
Biao Hong,Eryan Yang,Dongyuan Su,Jiasheng Ju,Xiaoteng Cui,Qixue Wang,Fei Tong,Jixing Zhao,Shixue Yang,Christine Cheng,Xin Lei,Menglin Xiao,Kaikai Yi,Zhan Qi,Yaqing Ding,Hanyi Xu,Longtao Cui,Chunsheng Kang
出处
期刊:Neuro-oncology
[Oxford University Press]
日期:2023-08-31
卷期号:26 (1): 100-114
被引量:4
标识
DOI:10.1093/neuonc/noad159
摘要
Abstract Background Temozolomide (TMZ) treatment efficacy in glioblastoma is determined by various mechanisms such as TMZ efflux, autophagy, base excision repair (BER) pathway, and the level of O6-methylguanine-DNA methyltransferase (MGMT). Here, we reported a novel small-molecular inhibitor (SMI) EPIC-1042 (C20H28N6) with the potential to decrease TMZ efflux and promote PARP1 degradation via autolysosomes in the early stage. Methods EPIC-1042 was obtained from receptor-based virtual screening. Co-immunoprecipitation and pull-down assays were applied to verify the blocking effect of EPIC-1042. Western blotting, co-immunoprecipitation, and immunofluorescence were used to elucidate the underlying mechanisms of EPIC-1042. In vivo experiments were performed to verify the efficacy of EPIC-1042 in sensitizing glioblastoma cells to TMZ. Results EPIC-1042 physically interrupted the interaction of PTRF/Cavin1 and caveolin-1, leading to reduced secretion of small extracellular vesicles (sEVs) to decrease TMZ efflux. It also induced PARP1 autophagic degradation via increased p62 expression that more p62 bound to PARP1 and specially promoted PARP1 translocation into autolysosomes for degradation in the early stage. Moreover, EPIC-1042 inhibited autophagy flux at last. The application of EPIC-1042 enhanced TMZ efficacy in glioblastoma in vivo. Conclusion EPIC-1042 reinforced the effect of TMZ by preventing TMZ efflux, inducing PARP1 degradation via autolysosomes to perturb the BER pathway and recruitment of MGMT, and inhibiting autophagy flux in the later stage. Therefore, this study provided a novel therapeutic strategy using the combination of TMZ with EPIC-1042 for glioblastoma treatment.
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