期刊
TOXICOLOGY LETTERS
卷 236, 期 1, 页码 43-59出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.toxlet.2015.04.015
关键词
FTY720; Glioblastoma; Autophagy; Apoptosis; Necroptosis
类别
资金
- National Natural Science Foundation of China [81070974, 81271377]
- Jiangsu Provincial Key Subject [X4200722]
- Jinling Hospital of Nanjing, China [2010Q017]
FTY720 is a potent immunosuppressant which has preclinical antitumor efficacy in various cancer models. However, its role in glioblastoma remains unclear. In the present study, we found that FTY720 induced extrinsic apoptosis, necroptosis and autophagy in human glioblastoma cells. Inhibition of autophagy by either RNA interference or chemical inhibitors attenuated FTY720-induced apoptosis and necrosis. Furthermore, autophagy, apoptosis and necrosis induction were dependent on reactive oxygen species-c-Jun N-terminal kinase-protein 53 (ROS-JNK-p53) loop mediated phosphatidylinositide 3-kinases/protein kinase B/mammalian target of rapamycin/p70S6 kinase (PI3K/AKT/mTOR/p70S6K) pathway. In addition, receptor-interacting protein 1 and 3 (RIP1 and RIP3) served as an upstream of ROS-JNK-p53 loop. However, the phosphorylation form of FTY720 induced autophagy but not apoptosis and necroptosis. Finally, the in vitro results were validated in vivo in xenograft mouse of glioblastoma cells. In conclusion, the current study provided novel insights into understanding the mechanisms and functions of FTY720-induced apoptosis, necroptosis and autophagy in human glioblastoma cells. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
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