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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

References

  1. Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359:492–507

    Article  CAS  PubMed  Google Scholar 

  2. Beck C, Robert I, Reina-San-Martin B, Schreiber V, Dantzer F (2014) Poly(ADP-ribose) polymerases in double-strand break repair: focus on PARP1, PARP2 and PARP3. Exp Cell Res 329:18–25

    Article  CAS  PubMed  Google Scholar 

  3. Fatokun AA, Dawson VL, Dawson TM (2014) Parthanatos: mitochondrial-linked mechanisms and therapeutic opportunities. Br J Pharmacol 171:2000–2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Galia A, Calogero AE, Condorelli R, Fraggetta F, La Corte A, Ridolfo F, Bosco P, Castiglione R et al (2012) PARP-1 protein expression in glioblastoma multiforme. Eur J Histochem 56, e9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kase M, Vardja M, Lipping A, Asser T, Jaal J (2011) Impact of PARP-1 and DNA-PK expression on survival in patients with glioblastoma multiforme. Radiother Oncol 101:127–131

    Article  CAS  PubMed  Google Scholar 

  6. Karpel-Massler G, Pareja F, Aimé P, Shu C, Chau L, Westhoff MA, Halatsch ME, Crary JF et al (2014) PARP inhibition restores extrinsic apoptotic sensitivity in glioblastoma. PLoS One 9, e114583

    Article  PubMed  PubMed Central  Google Scholar 

  7. Tentori L, Ricci-Vitiani L, Muzi A, Ciccarone F, Pelacchi F, Calabrese R, Runci D, Pallini R et al (2014) Pharmacological inhibition of poly(ADP-ribose) polymerase-1 modulates resistance of human glioblastoma stem cells to temozolomide. BMC Cancer 14:151

    Article  PubMed  PubMed Central  Google Scholar 

  8. Ma D, Lu B, Feng C, Wang C, Wang Y, Luo T, Feng J, Jia H et al (2016) Deoxypodophyllotoxin triggers parthanatos in glioma cells via induction of excessive ROS. Cancer Lett 371:194–204

    Article  CAS  PubMed  Google Scholar 

  9. Zhao N, Mao Y, Han G, Ju Q, Zhou L, Liu F, Xu Y, Zhao X (2015) YM155, a survivin suppressant, triggers PARP-dependent cell death (parthanatos) and inhibits esophageal squamous-cell carcinoma xenografts in mice. Oncotarget 6:18445–18459

    Article  PubMed  PubMed Central  Google Scholar 

  10. Lee Y, Kang HC, Lee BD, Lee YI, Kim YP, Shin JH (2014) Poly (ADP-ribose) in the pathogenesis of Parkinson’s disease. BMB Rep 47:424–432

    Article  PubMed  PubMed Central  Google Scholar 

  11. Mohammad G, Siddiquei MM, Abu El-Asrar AM (2013) Poly (ADP-ribose) polymerase mediates diabetes-induced retinal neuropathy. Mediat Inflamm 2013:510451

    Article  Google Scholar 

  12. Yang Z, Li L, Chen L, Yuan W, Dong L, Zhang Y, Wu H, Wang C (2014) PARP-1 mediates LPS-induced HMGB1 release by macrophages through regulation of HMGB1 acetylation. J Immunol 193:6114–6123

    Article  CAS  PubMed  Google Scholar 

  13. Lu P, Kamboj A, Gibson SB, Anderson CM (2014) Poly(ADP-ribose) polymerase-1 causes mitochondrial damage and neuron death mediated by Bnip3. J Neurosci 34:15975–15987

    Article  PubMed  Google Scholar 

  14. Wu P, Zhu X, Jin W, Hao S, Liu Q (2015) Oxaliplatin triggers necrosis as well as apoptosis in gastric cancer SGC-7901 cells. Biochem Biophys Res Commun 460:183–190

    Article  CAS  PubMed  Google Scholar 

  15. Chiu LY, Ho FM, Shiah SG, Chang Y, Lin WW (2011) Oxidative stress initiates DNA damager MNNG-induced poly(ADP-ribose)polymerase-1-dependent parthanatos cell death. Biochem Pharmacol 81:459–470

    Article  CAS  PubMed  Google Scholar 

  16. Akhiani AA, Werlenius O, Aurelius J, Movitz C, Martner A, Hellstrand K, Thorén FB (2014) Role of the ERK pathway for oxidant-induced parthanatos in human lymphocytes. PLoS One 9, e89646

    Article  PubMed  PubMed Central  Google Scholar 

  17. Zhang L, Wang H, Xu J, Zhu J, Ding K (2014) Inhibition of cathepsin S induces autophagy and apoptosis in human glioblastoma cell lines through ROS-mediated PI3K/AKT/mTOR/p70S6K and JNK signaling pathways. Toxicol Lett 228:248–259

    Article  CAS  PubMed  Google Scholar 

  18. Barbouti A, Doulias PT, Nousis L, Tenopoulou M, Galaris D (2002) DNA damage and apoptosis in hydrogen peroxide-exposed Jurkat cells: bolus addition versus continuous generation of H(2)O(2). Free Radic Biol Med 33:691–702

    Article  CAS  PubMed  Google Scholar 

  19. Mao Y, Song G, Cai Q, Liu M, Luo H, Shi M, Ouyang G, Bao S (2006) Hydrogen peroxide-induced apoptosis in human gastric carcinoma MGC803 cells. Cell Biol Int 30:332–337

    Article  CAS  PubMed  Google Scholar 

  20. Singh M, Sharma H, Singh N (2007) Hydrogen peroxide induces apoptosis in HeLa cells through mitochondrial pathway. Mitochondrion 7:367–373

    Article  CAS  PubMed  Google Scholar 

  21. Wang X, Wang J, Lin S, Geng Y, Wang J, Jiang B (2008) Sp1 is involved in H2O2-induced PUMA gene expression and apoptosis in colorectal cancer cells. J Exp Clin Cancer Res 27:44

    Article  PubMed  PubMed Central  Google Scholar 

  22. McKeague AL, Wilson DJ, Nelson J (2008) Staurosporine-induced apoptosis and hydrogen peroxide-induced necrosis in two human breast cell lines. Br J Cancer 88:125–131

    Article  Google Scholar 

  23. Datta K, Babbar P, Srivastava T, Sinha S, Chattopadhyay P (2002) p53 dependent apoptosis in glioma cell lines in response to hydrogen peroxide induced oxidative stress. Int J Biochem Cell Biol 34:148–157

    Article  CAS  PubMed  Google Scholar 

  24. Byun YJ, Kim SK, Kim YM, Chae GT, Jeong SW, Lee SB (2009) Hydrogen peroxide induces autophagic cell death in C6 glioma cells via BNIP3-mediated suppression of the mTOR pathway. Neurosci Lett 461:131–135

    Article  CAS  PubMed  Google Scholar 

  25. Chen Y, McMillan-Ward E, Kong J, Israels SJ, Gibson SB (2008) Oxidative stress induces autophagic cell death independent of apoptosis in transformed and cancer cells. Cell Death Differ 15:171–182

    Article  CAS  PubMed  Google Scholar 

  26. Zhang H, Kong X, Kang J, Su J, Li Y, Zhong J, Sun L (2009) Oxidative stress induces parallel autophagy and mitochondria dysfunction in human glioma U251 cells. Toxicol Sci 110:376–388

    Article  CAS  PubMed  Google Scholar 

  27. Lennicke C, Rahn J, Lichtenfels R, Wessjohann LA, Seliger B (2015) Hydrogen peroxide-production, fate and role in redox signaling of tumor cells. Cell Commun Signal 13:39

    Article  PubMed  PubMed Central  Google Scholar 

  28. Wang Y, Dawson VL, Dawson TM (2009) Poly(ADP-ribose) signals to mitochondrial AIF: a key event in parthanatos. Exp Neurol 218:193–202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Mashimo M, Kato J, Moss J (2013) ADP-ribosyl-acceptor hydrolase 3 regulates poly (ADP-ribose) degradation and cell death during oxidative stress. Proc Natl Acad Sci U S A 110:18964–18969

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhao H, Ning J, Lemaire A, Koumpa FS, Sun JJ, Fung A, Gu J, Yi B et al (2015) Necroptosis and parthanatos are involved in remote lung injury after receiving ischemic renal allografts in rats. Kidney Int 87:738–748

    Article  CAS  PubMed  Google Scholar 

  31. Andrabi SA, Kim NS, Yu S, Wang H, Koh DW, Sasaki M, Klaus JA, Otsuka T et al (2006) Poly(ADP-ribose) (PAR) polymer is a death signal. Proc Natl Acad Sci U S A 103:18308–18313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Andrabi SA, Umanah GK, Chang C, Stevens DA, Karuppagounder SS, Gagné JP, Poirier GG, Dawson VL et al (2014) Poly(ADP-ribose) polymerase-dependent energy depletion occurs through inhibition of glycolysis. Proc Natl Acad Sci U S A 28:10209–10214

    Article  Google Scholar 

  33. Paul M, Hemshekhar M, Thushara RM, Sundaram MS, NaveenKumar SK, Naveen S, Devaraja S, Somyajit K et al (2015) Methotrexate promotes platelet apoptosis via JNK-mediated mitochondrial damage: alleviation by N-acetylcysteine and N-acetylcysteine amide. PLoS One 10, e0127558

    Article  PubMed  PubMed Central  Google Scholar 

  34. Dixit D, Ghildiyal R, Anto NP, Sen E (2014) Chaetocin-induced ROS-mediated apoptosis involves ATM-YAP1 axis and JNK-dependent inhibition of glucose metabolism. Cell Death Dis 5, e1212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zhang C, Yang L, Wang XB, Wang JS, Geng YD, Yang CS, Kong LY (2013) Calyxin Y induces hydrogen peroxide-dependent autophagy and apoptosis via JNK activation in human non-small cell lung cancer NCI-H460 cells. Cancer Lett 340:51–62

    Article  CAS  PubMed  Google Scholar 

  36. Palit S, Kar S, Sharma G, Das PK (2015) Hesperetin induces apoptosis in breast carcinoma by triggering accumulation of ROS and activation of ASK1/JNK pathway. J Cell Physiol 230:1729–1739

    Article  CAS  PubMed  Google Scholar 

  37. Nomura J, Busso N, Ives A, Tsujimoto S, Tamura M, So A, Yamanaka Y (2013) Febuxostat, an inhibitor of xanthine oxidase, suppresses lipopolysaccharide-induced MCP-1 production via MAPK phosphatase-1-mediated inactivation of JNK. PLoS One 8, e75527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhou JY, Liu Y, Wu GS (2006) The role of mitogen-activated protein kinase phosphatase-1 in oxidative damage-induced cell death. Cancer Res 66:4888–4894

    Article  CAS  PubMed  Google Scholar 

  39. Hanawa N, Shinohara M, Saberi B, Gaarde WA, Han D, Kaplowitz N (2008) Role of JNK translocation to mitochondria leading to inhibition of mitochondria bioenergetics in acetaminophen-induced liver injury. J Biol Chem 283:13565–13577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Win S, Than TA, Le BH, García-Ruiz C, Fernandez-Checa JC, Kaplowitz N (2015) Sab (Sh3bp5) dependence of JNK mediated inhibition of mitochondrial respiration in palmitic acid induced hepatocyte lipotoxicity. J Hepatol 62:1367–1374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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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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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  • DOI: https://doi.org/10.1007/s12035-016-9926-y

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