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Toll样受体9-细胞外信号调节激酶-哺乳动物雷帕霉素靶蛋白信号通路对于由CpG寡脱氧核苷酸107联合照射诱导的胶质瘤细胞自噬性细胞死亡至关重要。

TLR9-ERK-mTOR signaling is critical for autophagic cell death induced by CpG oligodeoxynucleotide 107 combined with irradiation in glioma cells.

作者信息

Li Xiaoli, Cen Yanyan, Cai Yongqing, Liu Tao, Liu Huan, Cao Guanqun, Liu Dan, Li Bin, Peng Wei, Zou Jintao, Pang Xueli, Zheng Jiang, Zhou Hong

机构信息

Department of Pharmacology, College of Pharmacy, the Third Military Medical University, Chongqing 400038, China.

Department of Pharmacy, Institute of Surgery Research, Daping Hospital, the Third Military Medical University, Chongqing 400042, China.

出版信息

Sci Rep. 2016 Jun 2;6:27104. doi: 10.1038/srep27104.

DOI:10.1038/srep27104
PMID:27251306
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4890034/
Abstract

Synthetic oligodeoxynucleotides containing unmethylated CpG dinucleotides (CpG ODN) function as potential radiosensitizers for glioma treatment, although the underlying mechanism is unclear. It was observed that CpG ODN107, when combined with irradiation, did not induce apoptosis. Herein, the effect of CpG ODN107 + irradiation on autophagy and the related signaling pathways was investigated. In vitro, CpG ODN107 + irradiation induced autophagosome formation, increased the ratio of LC3 II/LC3 I, beclin 1 and decreased p62 expression in U87 cells. Meanwhile, CpG ODN107 also increased LC3 II/LC3 I expression in U251 and CHG-5 cells. In vivo, CpG ODN107 combined with local radiotherapy induced autophagosome formation in orthotopic transplantation tumor. Investigation of the molecular mechanisms demonstrated that CpG ODN107 + irradiation increased the levels of TLR9 and p-ERK, and decreased the level of p-mTOR in glioma cells. Further, TLR9-specific siRNA could affect the expressions of p-ERK and autophagy-related proteins in glioma cells. Taken together, CpG ODN107 combined with irradiation could induce autophagic cell death, and this effect was closely related to the TLR9-ERK-mTOR signaling pathway in glioma cells, providing new insights into the investigation mechanism of CpG ODN.

摘要

含有未甲基化CpG二核苷酸的合成寡脱氧核苷酸（CpG ODN）作为胶质瘤治疗的潜在放射增敏剂发挥作用，尽管其潜在机制尚不清楚。据观察，CpG ODN107与辐射联合时不会诱导细胞凋亡。在此，研究了CpG ODN107 + 辐射对自噬及相关信号通路的影响。在体外，CpG ODN107 + 辐射诱导U87细胞中自噬体形成，增加LC3 II/LC3 I、beclin 1的比例并降低p62表达。同时，CpG ODN107也增加U251和CHG-5细胞中LC3 II/LC3 I的表达。在体内，CpG ODN107与局部放疗联合可诱导原位移植瘤中自噬体形成。分子机制研究表明，CpG ODN107 + 辐射可增加胶质瘤细胞中TLR9和p-ERK的水平，并降低p-mTOR的水平。此外，TLR9特异性siRNA可影响胶质瘤细胞中p-ERK和自噬相关蛋白的表达。综上所述，CpG ODN107与辐射联合可诱导自噬性细胞死亡，且这种作用与胶质瘤细胞中的TLR9-ERK-mTOR信号通路密切相关，为CpG ODN的作用机制研究提供了新的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/68a7/4890034/f3869c1aa505/srep27104-f8.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/68a7/4890034/f3869c1aa505/srep27104-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/68a7/4890034/4b5849513acd/srep27104-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/68a7/4890034/12f4b3bb8513/srep27104-f2.jpg
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