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.
Highlights
Temozolomide (TMZ) is the most commonly used chemical drug for glioblastoma (GBM) treatment in clinic [1, 2], almost all of the patients suffered from therapy failure as the results of TMZ chemoresistance [3, 4], which could be attributed to the alterations of cancer associated genes expression patterns [5]
By performing the CCK-8 assay, we found that the proliferation abilities in TMZ-sensitive GBM (TS-GBM) cells, instead of TMZresistant GBM (TR-GBM) cells, were significantly inhibited by high-dose TMZ stimulation in a time-dependent manner (Fig. 1a–f )
GBM-derived stem cells (GSCs) derived PD‐L1 containing exosomes promoted TMZ‐resistance in GBM cells Given the fact that GSCs derived exosomes contributed to TMZ resistance in GBM [8,9,10], as shown in Fig. 2a, we isolated and purified exosomes from TS-GBM and TR-GBM cells based on the protocols provided by the previous publications [8,9,10]
Summary
Temozolomide (TMZ) is the most commonly used chemical drug for glioblastoma (GBM) treatment in clinic [1, 2], almost all of the patients suffered from therapy failure as the results of TMZ chemoresistance [3, 4], which could be attributed to the alterations of cancer associated genes expression patterns [5]. TMZ-resistance seriously limited the therapeutic efficacy of TMZ, and brought huge health burden to GBM patients [3, 4]. Researchers agreed that uncovering the underlying mechanisms of TMZ-resistance will help to solve this problem [5], and the existed literatures suggested that GBM-derived stem cells (GSCs) contributed to TMZ-resistance in GBM [6, 7]. On the one hand, GSCs were characterized by selfrenewal abilities, which could differentiate into TMZresistant GBM (TR-GBM) cells under TMZ pressure [6, 7]. Zheng et al Cell Biosci (2021) 11:63 through secreting exosomes, which increased TMZresistance in the GBM cells [8,9,10]. Based on the above information, we focused on investigating the role of GSCs-derived exosomes in regulating TMZ-resistance in GBM
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