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Molecular Neurobiology

, Volume 54, Issue 5, pp 3492–3505 | Cite as

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

  • Linjie Zheng
  • Chen Wang
  • Tianfei Luo
  • Bin Lu
  • Hongxi Ma
  • Zijian Zhou
  • Dong Zhu
  • Guangfan Chi
  • Pengfei GeEmail author
  • Yinan LuoEmail author
Article

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.

Keywords

PARP-1 JNK ROS Parthanatos Glioma Oxidative stress 

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

Notes

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).

Compliance with Ethical Standards

Conflict of Interests

The authors declare that they have no conflict of interests.

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Linjie Zheng
    • 1
    • 2
  • Chen Wang
    • 1
    • 2
  • Tianfei Luo
    • 2
    • 3
  • Bin Lu
    • 1
    • 2
  • Hongxi Ma
    • 4
  • Zijian Zhou
    • 1
    • 2
  • Dong Zhu
    • 5
  • Guangfan Chi
    • 6
  • Pengfei Ge
    • 1
    • 2
    Email author
  • Yinan Luo
    • 1
    Email author
  1. 1.Department of NeurosurgeryFirst Hospital of Jilin UniversityChangchunChina
  2. 2.Research Center of NeuroscienceFirst Hospital of Jilin UniversityChangchunChina
  3. 3.Department of NeurologyFirst Hospital of Jilin UniversityChangchunChina
  4. 4.Department of PathologyFirst Hospital of Jilin UniversityChangchunChina
  5. 5.Department of OrthopaedicsFirst Hospital of Jilin UniversityChangchunChina
  6. 6.Key Laboratory of Pathobiology, Ministry of EducationJilin UniversityChangchunChina

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