NDLI: Glioblastoma stem cell (GSC)-derived PD-L1-containing exosomes activates AMPK/ULK1 pathway mediated autophagy to increase temozolomide-resistance in glioblastoma

Content Provider	Springer Nature : BioMed Central
Author	Zheng, Yong Liu, Liang Wang, Yan Xiao, Shan Mai, Rongkang Zhu, Zifeng Cao, Yiyao
Abstract	Temozolomide (TMZ)-resistance hampers the therapeutic efficacy of this drug for glioblastoma (GBM) treatment in clinic, and emerging evidences suggested that exosomes from GBM-derived stem cells (GSCs) contributed to this process, but the detailed mechanisms are still largely unknown. In the present study, we reported that GSCs derived programmed death-ligand 1 (PD-L1) containing exosomes activated AMPK/ULK1 pathway mediated protective autophagy enhanced TMZ-resistance in GBM in vitro and in vivo. Specifically, we noticed that continuous low-dose TMZ stimulation promoted GSCs generation and PD-L1 containing exosomes (PD-L1-ex) secretion in GBM cells, and that PD-L1-ex inhibited cell apoptosis and promoted cell autophagy to increased TMZ-resistance in GBM cells, which were reversed by co-treating cells with the autophagy inhibitor 3-methyladenine (3-MA). Consistently, upregulation of PD-L1 also increased TMZ-resistance in TS-GBM cells, and silencing of PD-L1 sensitized TR-GBM cells to TMZ. In addition, PD-L1-ex activated AMPK/ULK1 pathway to induce autophagy in TMZ treated GBM cells, and the inhibitors for AMPK (compound C) and ULK1 (SBI-0206965) promoted cell apoptosis in GBM cells co-treated with PD-L1-ex and high-dose TMZ. Finally, we evidenced that PD-L1-ex promoted tumor growth and Ki67 protein expressions to increase TMZ-resistance in GBM in vivo. Collectively, we concluded that GSCs-derived PD-L1-ex activated AMPK1/ULK1 signaling cascade mediated autophagy to increase TMZ-resistance in GBM, and this study provided potential strategies to improve the therapeutic efficacy of TMZ in GBM.
Related Links	https://cellandbioscience.biomedcentral.com/counter/pdf/10.1186/s13578-021-00575-8.pdf
Ending Page	12
Page Count	12
Starting Page	1
File Format	HTM / HTML
ISSN	20453701
DOI	10.1186/s13578-021-00575-8
Journal	Cell & Bioscience
Issue Number	1
Volume Number	11
Language	English
Publisher	BioMed Central
Publisher Date	2021-03-31
Access Restriction	Open
Subject Keyword	Cell Biology Microbiology Stem Cells Neurobiology Proteomics Glioblastoma GBM-derived stem cells Temozolomide Programmed death-ligand 1 Autophagy
Content Type	Text
Resource Type	Article
Subject	Biochemistry, Genetics and Molecular Biology
Journal Impact Factor	6.1/2023
5-Year Journal Impact Factor	7/2023

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