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Inhibition of c-Jun N-terminal kinase enhances temozolomide-induced cytotoxicity in human glioma cells

  • Laboratory Investigation - Human/animal tissue
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Abstract

Previous studies have revealed that p38, a member of the family of stress-activated protein kinases (SAPKs), cooperates with the Chk1-pathway to bring about temozolomide (TMZ)-induced G2 arrest, and that the inhibition of either pathway alone is sufficient to sensitize U87MG glioma cells to TMZ-induced cytotoxicity. c-Jun N-terminal kinase (JNK), another SAPK, has been reported to have several roles of cell survival, oncogenesis, growth, differentiation and cell death. To elucidate the functions of JNK in glioma cells treated with TMZ, we analyzed alterations in JNK and the effect of modification of JNK in U87MG human glioma cells treated with TMZ. We found that JNK was phosphorylated 1–2 days after TMZ treatment and that pretreatment (for 24 h) and post-treatment (for 72 h) with a JNK inhibitor SP600125 at a concentration of 200 nM or higher remarkably reduced clonogenicity in the TMZ-treated cells. The phosphorylation of the JNK target protein c-Jun, but not of ATF-2, was inhibited by this concentration of SP600125. Therefore JNK was proved to have a role of survival in glioma cells treated with TMZ, and c-Jun-related responses were suggested to be more important in the JNK-mediated survival of glioma cells with DNA damage. SP600125 amplified the percentage of senescence-like cells and of mitotic catastrophe cells in TMZ-treated U87MG and U87MG-E6 cells, respectively, suggesting that the enhancement of TMZ-induced cytotoxicity by a JNK inhibitor in glioma cells is induced (at least in part) by the potentiation of cell death pathways induced by TMZ alone. Further investigation based on the present data may provide a viable approach for enhancing TMZ-induced cytotoxicity in human gliomas.

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References

  1. Hirose Y, Berger MS, Pieper RO (2001) Abrogation of the Chk1-mediated G2 checkpoint pathway potentiates temozolomide-induced toxicity in a p53-independent manner in human glioblastoma ells. Cancer Res 61:5843–5849

    CAS  PubMed  Google Scholar 

  2. Hirose Y, Berger MS, Pieper RO (2001) p53 effects both the duration of G2/M arrest and the fate of temozolomide-treated human glioblastoma cells. Cancer Res 61:1957–1963

    CAS  PubMed  Google Scholar 

  3. Hirose Y, Kreklau EL, Erickson LC et al (2003) Delayed repletion of O6-methylguanine-DNA methyltransferase resulting in failure to protect the human glioblastoma cell line SF767 from temozolomide-induced cytotoxicity. J Neurosurg 98:591–598

    Article  CAS  PubMed  Google Scholar 

  4. Stupp R, Mason WP, van den Bent MJ, European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups, National Cancer Institute of Canada Clinical Trials Group et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996. doi:10.1056/NEJMoa043330

    Article  CAS  PubMed  Google Scholar 

  5. Brozovic A, Osmak M (2007) Activation of mitogen-activated protein kinases by cisplatin and their role in cisplatin-resistance. Cancer Lett 251:1–16. doi:10.1016/j.canlet.2006.10.007

    Article  CAS  PubMed  Google Scholar 

  6. Kapoor GS, O’Rourke DM (2003) Receptor tyrosine kinase signaling in gliomagenesis: pathobiology and therapeutic approaches. Cancer Biol Ther 2:330–342

    Article  CAS  PubMed  Google Scholar 

  7. Mandell JW, Hussaini IM, Zecevic M et al (1998) In situ visualization of intratumor growth factor signaling: immunohistochemical localization of activated ERK/MAP kinase in glial neoplasms. Am J Pathol 153:1411–1423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Potapova O, Gorospe M, Bost F et al (2000) c-Jun N-terminal kinase is essential for growth of human T98G glioblastoma cells. J Biol Chem 275:24767–24775. doi:10.1074/jbc.M904591199

    Article  CAS  PubMed  Google Scholar 

  9. Tsuiki H, Tnani M, Okamoto I et al (2003) Constitutively active forms of c-Jun NH2-terminal kinase are expressed in primary glial tumors. Cancer Res 63:250–255

    CAS  PubMed  Google Scholar 

  10. Cui J, Han SY, Wang C et al (2006) c-Jun NH(2)-terminal kinase 2alpha2 promotes the tumorigenicity of human glioblastoma cells. Cancer Res 66:10024–10031. doi:10.1158/0008-5472.CAN-06-0136

    Article  CAS  PubMed  Google Scholar 

  11. Gupta S, Barrett T, Whitmarsh AJ (1996) Selective interaction of JNK protein kinase isoforms with transcription factors. EMBO J 15:2760–2770

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Bennett BL, Sasaki DT, Murray BW et al (2001) SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci USA 98:13681–13686. doi:10.1073/pnas.251194298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Liu J, Lin A (2005) Role of JNK activation in apoptosis: a double-edged sword. Cell Res 15:36–42. doi:10.1038/sj.cr.7290262

    Article  PubMed  Google Scholar 

  14. Hirose Y, Katayama M, Stokoe D et al (2003) The p38 mitogen-activated protein kinase pathway links the DNA mismatch repair system to the G2 checkpoint and to resistance to chemotherapeutic DNA-methylating agents. Mol Cell Biol 23:8306–8315. doi:10.1128/MCB.23.22.8306-8315.2003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dimri GP, Lee X, Basile G et al (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 92:9363–9367. doi:10.1073/pnas.92.20.9363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ohgaki H, Dessen P, Jourde B et al (2004) Genetic pathways to glioblastoma: a population-based study. Cancer Res 64:6892–6899. doi:10.1158/0008-5472.CAN-04-1337

    Article  CAS  PubMed  Google Scholar 

  17. Fuchs SY, Xie B, Adler V et al (1997) c-Jun NH2-terminal kinases target the ubiquitination of their associated transcription factors. J Biol Chem 272:32163–32168. doi:10.1074/jbc.272.51.32163

    Article  CAS  PubMed  Google Scholar 

  18. Bhoumik A, Ivanov V, Ronai Z (2001) Activating transcription factor 2-derived peptides alter resistance of human tumor cell lines to ultraviolet irradiation and chemical treatment. Clin Cancer Res 7:331–342

    CAS  PubMed  Google Scholar 

  19. Dass CR, Khachigian LM, Choong PF (2008) c-Jun knockdown sensitizes osteosarcoma to doxorubicin. Mol Cancer Ther 7:1909–1912. doi:10.1158/1535-7163.MCT-08-0086

    Article  CAS  PubMed  Google Scholar 

  20. Hirose Y, Katayama M, Mirzoeva OK et al (2005) Akt activation suppresses Chk2-mediated, methylating agent-induced G2 arrest and protects from temozolomide-induced mitotic catastrophe and cellular senescence. Cancer Res 65:4861–4869. doi:10.1158/0008-5472.CAN-04-2633

    Article  CAS  PubMed  Google Scholar 

  21. Katayama M, Kawaguchi T, Berger MS et al (2007) DNA damaging agent-induced autophagy produces a cytoprotective adenosine triphosphate surge in malignant glioma cells. Cell Death Differ 14:548–558. doi:10.1038/sj.cdd.4402030

    Article  CAS  PubMed  Google Scholar 

  22. Chan TA, Hermeking H, Lengauer C et al (1999) 14-3-3Sigma is required to prevent mitotic catastrophe after DNA damage. Nature 401:616–620. doi:10.1038/44188

    Article  CAS  PubMed  Google Scholar 

  23. Potapova O, Haghighi A, Bost F et al (1997) The Jun kinase/stress-activated protein kinase pathway functions to regulate DNA repair and inhibition of the pathway sensitizes tumor cells to cisplatin. J Biol Chem 272:14041–14044. doi:10.1074/jbc.272.22.14041

    Article  CAS  PubMed  Google Scholar 

  24. Teraishi F, Zhang L, Guo W et al (2005) Activation of c-Jun NH2-terminal kinase is required for gemcitabine’s cytotoxic effect in human lung cancer H1299 cells. FEBS Lett 579:6681–6687. doi:10.1016/j.febslet.2005.10.064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hayakawa J, Ohmichi M, Kurachi H et al (1999) Inhibition of extracellular signal-regulated protein kinase or c-Jun N-terminal protein kinase cascade, differentially activated by cisplatin, sensitizes human ovarian cancer cell line. J Biol Chem 274:31648–31654. doi:10.1074/jbc.274.44.31648

    Article  CAS  PubMed  Google Scholar 

  26. Kook SH, Son YO, Jang YS et al (2008) Inhibition of c-Jun N-terminal kinase sensitizes tumor cells to flavonoid-induced apoptosis through down-regulation of JunD. Toxicol Appl Pharmacol 227:468–476. doi:10.1016/j.taap.2007.11.004

    Article  CAS  PubMed  Google Scholar 

  27. Kuntzen C, Sonuc N, De Toni EN et al (2005) Inhibition of c-Jun-N-terminal-kinase sensitizes tumor cells to CD95-induced apoptosis and induces G2/M cell cycle arrest. Cancer Res 65:6780–6788. doi:10.1158/0008-5472.CAN-04-2618

    Article  CAS  PubMed  Google Scholar 

  28. Li F, Meng L, Zhou J et al (2005) Reversing chemoresistance in cisplatin-resistant human ovarian cancer cells: a role of c-Jun NH2-terminal kinase 1. Biochem Biophys Res Commun 335:1070–1077. doi:10.1016/j.bbrc.2005.07.169

    Article  CAS  PubMed  Google Scholar 

  29. Chen YR, Wang X, Templeton D et al (1996) The role of c-Jun N-terminal kinase (JNK) in apoptosis induced by ultraviolet C and gamma radiation. Duration of JNK activation may determine cell death and proliferation. J Biol Chem 271:31929–31936. doi:10.1074/jbc.271.50.31929

    Article  CAS  PubMed  Google Scholar 

  30. Lee YJ, Shukla SD (2005) Pro- and anti-apoptotic roles of c-Jun N-terminal kinase (JNK) in ethanol and acetaldehyde exposed rat hepatocytes. Eur J Pharmacol 508:31–45. doi:10.1016/j.ejphar.2004.12.006

    Article  CAS  PubMed  Google Scholar 

  31. Ventura JJ, Hübner A, Zhang C et al (2006) Chemical genetic analysis of the time course of signal transduction by JNK. Mol Cell 21:701–710. doi:10.1016/j.molcel.2006.01.018

    Article  CAS  PubMed  Google Scholar 

  32. Potapova O, Gorospe M, Dougherty RH et al (2000) Inhibition of c-Jun N-terminal kinase 2 expression suppresses growth and induces apoptosis of human tumor cells in a p53-dependent manner. Mol Cell Biol 20:1713–1722. doi:10.1128/MCB.20.5.1713-1722.2000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tafolla E, Wang S, Wong B et al (2005) JNK1 and JNK2 oppositely regulate p53 in signaling linked to apoptosis triggered by an altered fibronectin matrix: JNK links FAK and p53. J Biol Chem 280:19992–19999. doi:10.1074/jbc.M500331200

    Article  CAS  PubMed  Google Scholar 

  34. Das M, Jiang F, Sluss HK et al (2007) Suppression of p53-dependent senescence by the JNK signal transduction pathway. Proc Natl Acad Sci USA 104:15759–15764. doi:10.1073/pnas.0707782104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Cui J, Zhang M, Zhang YQ et al (2007) JNK pathway: diseases and therapeutic potential. Acta Pharmacol Sin 28:601–608. doi:10.1111/j.1745-7254.2007.00579.x

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by a grant from Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science (Type B, No. 20390391) and by funding from the Japan Brain Foundation.

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Authors and Affiliations

  1. Department of Neurosurgery, Keio University, Tokyo, Japan

    Shigeo Ohba & Takeshi Kawase

  2. Department of Neurosurgery, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan

    Yuichi Hirose & Hirotoshi Sano

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  1. Shigeo Ohba
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  2. Yuichi Hirose
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Correspondence to Yuichi Hirose.

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Ohba, S., Hirose, Y., Kawase, T. et al. Inhibition of c-Jun N-terminal kinase enhances temozolomide-induced cytotoxicity in human glioma cells. J Neurooncol 95, 307–316 (2009). https://doi.org/10.1007/s11060-009-9929-x

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  • DOI: https://doi.org/10.1007/s11060-009-9929-x

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