title: Pristimerin triggers AIF-dependent programmed necrosis in glioma cells via activation of JNK.
abstract: Programmed necrosis is established as a new form of programmed cell death and is emerging as a new strategy of treatment for cancers. Pristimerin is a natural chemical with anti-tumor effect despite the fact that its mechanism remains poorly understood. In this study, we used glioma cell lines and mice model of xenograft glioma to investigate the effect of pristimerin on glioma and its underlying mechanism. We found that pristimerin inhibited the viabilities of glioma cells in vitro and the growth of xenograft gliomas in vivo, which was accompanied by upregulation of JNK and phosphor-JNK, nuclear accumulation of AIF, and elevation in the ratio of Bax/Bcl-2. In vitro studies showed that pristimerin induced necrosis in glioma cells, as well as mitochondrial depolarization, overproduction of ROS and reduction of GSH. Ablation of AIF level with SiRNA mitigated pristimerin-induced nuclear accumulation of AIF and prevented necrosis in glioma cells. Moreover, pharmacological inhibition of JNK with SP600125 or knockdown of its level with SiRNA reversed mitochondrial depolarization attenuated the elevation of Bax/Bcl-2 and suppressed nuclear accumulation of AIF. Further, inhibition of ROS with NAC not only rescued glioma cell necrosis but also suppressed JNK activation, mitigated Bax/Bcl-2 ratio, maintained mitochondrial membrane potential, and inhibited AIF translocation into nucleus. Therefore, we demonstrated first in this study that pristimerin triggered AIF-dependent necroptosis in glioma cells via induction of mitochondrial dysfunction by activation of JNK through overproduction of ROS. These results suggest that pristimerin has potential therapeutic effects on glioma.
authors: Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China.
authors: Hongwei
authors: H
authors: Zhao
authors: Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China.
authors: Chen
authors: C
authors: Wang
authors: Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China.
authors: Bin
authors: B
authors: Lu
authors: Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China.
authors: Zijian
authors: Z
authors: Zhou
authors: Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China.
authors: Yong
authors: Y
authors: Jin
authors: Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China.
authors: Zongqi
authors: Z
authors: Wang
authors: Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China.
authors: Linjie
authors: L
authors: Zheng
authors: Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China.
authors: Kai
authors: K
authors: Liu
authors: Research Center of Neuroscience, First Hospital of Jilin University, Changchun 130021, China; Department of Neurology, First Hospital of Jilin University, Changchun 130021, China.
authors: Tianfei
authors: T
authors: Luo
authors: Department of Orthopaedics, First Hospital of Jilin University, Changchun 130021, China.
authors: Dong
authors: D
authors: Zhu
authors: Department of Orthopaedics, First Hospital of Jilin University, Changchun 130021, China; Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun 130021, China.
authors: Guangfan
authors: G
authors: Chi
authors: Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China; Research Center of Neuroscience, First Hospital of Jilin University, Changchun 130021, China.
authors: Yinan
authors: Y
authors: Luo
authors: Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China; Research Center of Neuroscience, First Hospital of Jilin University, Changchun 130021, China. Electronic address: pengfeige@gmail.com.
authors: Pengfei
authors: P
authors: Ge
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009336:Necrosis; D053978:Pentacyclic Triterpenes; D051381:Rats; D014315:Triterpenes / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C494829:AIFM1 protein, human; D000970:Antineoplastic Agents; D051033:Apoptosis Inducing Factor; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D048670:MAP Kinase Kinase 4; C050414:celastrol
keywords: Apoptosis inducing factor (AIF); Glioma; Pristimerin; Programmed necrosis; ROS; c-Jun terminal kinase (JNK)