Zhang Li, Wang Handong, Ding Ke, Xu Jianguo
Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, China.
Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, China.
Toxicol Lett. 2015 Jul 2;236(1):43-59. doi: 10.1016/j.toxlet.2015.04.015. Epub 2015 May 1.
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.
FTY720是一种强效免疫抑制剂，在多种癌症模型中具有临床前抗肿瘤疗效。然而，其在胶质母细胞瘤中的作用仍不清楚。在本研究中，我们发现FTY720可诱导人胶质母细胞瘤细胞发生外源性凋亡、坏死性凋亡和自噬。通过RNA干扰或化学抑制剂抑制自噬可减弱FTY720诱导的凋亡和坏死。此外，自噬、凋亡和坏死的诱导依赖于活性氧-c-Jun氨基末端激酶-蛋白53（ROS-JNK-p53）环介导的磷脂酰肌醇3-激酶/蛋白激酶B/雷帕霉素哺乳动物靶标/p70S6激酶（PI3K/AKT/mTOR/p70S6K）途径。此外，受体相互作用蛋白1和3（RIP1和RIP3）作为ROS-JNK-p53环的上游。然而，FTY720的磷酸化形式诱导自噬，但不诱导凋亡和坏死性凋亡。最后，体外结果在胶质母细胞瘤细胞异种移植小鼠体内得到验证。总之，本研究为理解FTY720诱导人胶质母细胞瘤细胞凋亡、坏死性凋亡和自噬的机制及功能提供了新的见解。
