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JNK Activation Contributes to Oxidative Stress-Induced Parthanatos in Glioma Cells via Increase of Intracellular ROS Production

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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 H2O2 to investigate the role of JNK in glioma cell parthanatos induced by oxidative stress. We found that exposure to H2O2 not 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 H2O2 exposure 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.

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Abbreviations

PARP-1:

Poly(ADP-ribose) synthetase 1

PAR:

Poly(ADP-ribose)

NAD+:

Nicotinamide adenine dinucleotide

MAPK:

Mitogen-activated protein kinase

JNK:

c-Jun-N-terminal protein kinase

ERK1/2:

Extracellular signal regulated kinases 1 and 2

AIF:

Apoptosis inducing factor

RIP-1:

Receptor interacting protein-1

ROS:

Reactive oxygen species

LDH:

Lactate dehydrogenase

Nec-1:

Necrostatin-1

3AB:

3-Aminobenzamide

NAC:

N-acetyl-l-cysteine

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Acknowledgments

This work was supported by the National Nature Science Foundation of China (81171234, 81372697, 11432016, and 11272134), the Changbaishan Scholar Project of Jilin province (2013026), the Scientific Research Foundation of Jilin province (20150414013GH, 20121809), and the Bethune project B of Jilin University (no.2012203).

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Authors and Affiliations

  1. Department of Neurosurgery, First Hospital of Jilin University, 71 Xinmin Avenue, Changchun, 130021, Jilin Province, China

    Linjie Zheng, Chen Wang, Bin Lu, Zijian Zhou, Pengfei Ge & Yinan Luo

  2. Research Center of Neuroscience, First Hospital of Jilin University, Changchun, 130021, China

    Linjie Zheng, Chen Wang, Tianfei Luo, Bin Lu, Zijian Zhou & Pengfei Ge

  3. Department of Neurology, First Hospital of Jilin University, Changchun, 130021, China

    Tianfei Luo

  4. Department of Pathology, First Hospital of Jilin University, Changchun, 130021, China

    Hongxi Ma

  5. Department of Orthopaedics, First Hospital of Jilin University, Changchun, 130021, China

    Dong Zhu

  6. Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, 130021, China

    Guangfan Chi

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  1. Linjie Zheng
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Correspondence to Pengfei Ge or Yinan Luo.

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Zheng, L., Wang, C., Luo, T. et al. JNK Activation Contributes to Oxidative Stress-Induced Parthanatos in Glioma Cells via Increase of Intracellular ROS Production. Mol Neurobiol 54, 3492–3505 (2017). https://doi.org/10.1007/s12035-016-9926-y

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