title: JNK Activation Contributes to Oxidative Stress-Induced Parthanatos in Glioma Cells via Increase of Intracellular ROS Production.
abstract: Parthanatos is a form of PARP-1-dependent programmed cell death. The induction of parthanatos is emerging as a new strategy to kill gliomas which are the most common type of primary malignant brain tumor. Oxidative stress is thought to be a critical factor triggering parthanatos, but its underlying mechanism is poorly understood. In this study, we used glioma cell lines and H2O2to investigate the role of JNK in glioma cell parthanatos induced by oxidative stress. We found that exposure to H2O2not only induced intracellular accumulation of ROS but also resulted in glioma cell death in a concentration- and incubation time-dependent manner, which was accompanied with cytoplasmic formation of PAR polymer, expressional upregulation of PARP-1, mitochondrial depolarization, and AIF translocation to nucleus. Pharmacological inhibition of PARP-1 with 3AB or genetic knockdown of its level with siRNA rescued glioma cell death, as well as suppressed cytoplasmic accumulation of PAR polymer and nuclear translocation of AIF, which were consistent with the definition of parthanatos. Moreover, the phosphorylated level of JNK increased markedly with the extension of H2O2exposure time. Either attenuation of intracellular ROS with antioxidant NAC or inhibition of JNK phosphorylation with SP600125 or JNK siRNA could significantly prevent H2O2-induced parthanatos in glioma cells. Additionally, inhibition of JNK with SP600125 alleviated intracellular accumulation of ROS and attenuated mitochondrial generation of superoxide. Thus, we demonstrated that JNK activation contributes to glioma cell parthanatos caused by oxidative stress via increase of intracellular ROS generation.
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, 71 Xinmin Avenue, Changchun, 130021, Jilin Province, China.|Research Center of Neuroscience, First Hospital of Jilin University, Changchun, 130021, China.
authors.forename: Linjie
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, 71 Xinmin Avenue, Changchun, 130021, Jilin Province, China.|Research Center of Neuroscience, First Hospital of Jilin University, Changchun, 130021, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Research Center of Neuroscience, First Hospital of Jilin University, Changchun, 130021, China.|Department of Neurology, First Hospital of Jilin University, Changchun, 130021, China.
authors.forename: Tianfei
authors.initials: T
authors.lastname: Luo
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, 71 Xinmin Avenue, Changchun, 130021, Jilin Province, China.|Research Center of Neuroscience, First Hospital of Jilin University, Changchun, 130021, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Lu
authors.affiliation: Department of Pathology, First Hospital of Jilin University, Changchun, 130021, China.
authors.forename: Hongxi
authors.initials: H
authors.lastname: Ma
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, 71 Xinmin Avenue, Changchun, 130021, Jilin Province, China.|Research Center of Neuroscience, First Hospital of Jilin University, Changchun, 130021, China.
authors.forename: Zijian
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Orthopaedics, First Hospital of Jilin University, Changchun, 130021, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, 130021, China.
authors.forename: Guangfan
authors.initials: G
authors.lastname: Chi
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, 71 Xinmin Avenue, Changchun, 130021, Jilin Province, China. gepf@jlu.edu.cn.|Research Center of Neuroscience, First Hospital of Jilin University, Changchun, 130021, China. gepf@jlu.edu.cn.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Ge
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, 71 Xinmin Avenue, Changchun, 130021, Jilin Province, China. yinanluo@gmail.com.
authors.forename: Yinan
authors.initials: Y
authors.lastname: Luo
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D001932:Brain Neoplasms / Q000201:enzymology* / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005910:Glioma / Q000201:enzymology* / Q000473:pathology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D042541:Intracellular Space / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism
chemical_list: D000975:Antioxidants; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013481:Superoxides; D006861:Hydrogen Peroxide; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D048031:JNK Mitogen-Activated Protein Kinases; D000111:Acetylcysteine
keywords: Glioma; JNK; Oxidative stress; PARP-1; Parthanatos; ROS