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Temozolomide and irradiation combined treatment-induced Nrf2 activation increases chemoradiation sensitivity in human glioblastoma cells

  • Laboratory Investigation
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Abstract

Resistance to chemoradiotherapy is a major obstacle to successful treatment of glioblastoma. Recently, the role of NF-E2-related factor 2 (Nrf2) in enhancing chemoradiation sensitivity has been reported in several types of cancers. Here, we investigated whether temozolomide (TMZ) and irradiation (IR) combined treatment induced Nrf2 activation in human glioblastoma cells. And we further performed a preliminary study about the effect of Nrf2 on chemoradiation sensitivity. Immunohistochemical staining for Nrf2 in paired clinical specimens showed that TMZ and IR combined treatment increased the expression and nuclear localization of Nrf2 in human glioblastoma tissues. Moreover, we found nuclear Nrf2 expression in the glioblastoma tissues obtained from the patients undergoing TMZ and IR combined treatment was associated with the time to tumor recurrence. In vitro, we further verified these findings. First, we detected increased nuclear localization of Nrf2 following treatment with TMZ+IR in human glioblastoma cell lines. Second, we demonstrated TMZ+IR increased the levels of Nrf2 protein in both nuclear and cytoplasmic fractions of U251 cells and induced Nrf2 target genes expression. Finally, downregulating Nrf2 expression increased TMZ+IR-induced cell death in the U251 cells. These findings suggest TMZ+IR combined treatment induces Nrf2 activation in human glioblastoma cells. The activation of Nrf2 may be associate with enhancing chemoradiation sensitivity in human glioblastoma cell. Blocking Nrf2 activation may be a promising method enhancing chemoradiation sensitivity of glioblastoma cells.

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References

  1. Lau A, Villeneuve NF, Sun Z, Wong PK, Zhang DD (2008) Dual roles of Nrf2 in cancer. Pharmacol Res 58:262–270. doi:10.1016/j.phrs.2008.09.003

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Lee JM, Johnson JA (2004) An important role of Nrf2-ARE pathway in the cellular defense mechanism. J Biochem Mol Biol 37:139–143

    Article  CAS  PubMed  Google Scholar 

  3. Niture SK, Kaspar JW, Shen J, Jaiswal AK (2010) Nrf2 signaling and cell survival. Toxicol Appl Pharmacol 244:37–42. doi:10.1016/j.taap.2009.06.009

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Akhdar H, Loyer P, Rauch C, Corlu A, Guillouzo A, Morel F (2009) Involvement of Nrf2 activation in resistance to 5-fluorouracil in human colon cancer HT-29 cells. Eur J Cancer 45:2219–2227. doi:10.1016/j.ejca.2009.05.017

    Article  CAS  PubMed  Google Scholar 

  5. Singh A, Bodas M, Wakabayashi N, Bunz F, Biswal S (2010) Gain of Nrf2 function in non-small-cell lung cancer cells confers radioresistance. Antioxid Redox Signal 13:1627–1637. doi:10.1089/ars 2010.3219

    Article  CAS  PubMed  Google Scholar 

  6. Cho JM, Manandhar S, Lee HR, Park HM, Kwak MK (2008) Role of the Nrf2-antioxidant system in cytotoxicity mediated by anticancer cisplatin: implication to cancer cell resistance. Cancer Lett 260:96–108. doi:10.1016/j.canlet.2007.10.022

    Article  CAS  PubMed  Google Scholar 

  7. Homma S, Ishii Y, Morishima Y, Yamadori T, Matsuno Y, Haraguchi N, Kikuchi N, Satoh H, Sakamoto T, Hizawa N, Itoh K, Yamamoto M (2009) Nrf2 enhances cell proliferation and resistance to anticancer drugs in human lung cancer. Clin Cancer Res 15:3423–3432. doi:10.1158/1078-0432.CCR-08-2822

    Article  CAS  PubMed  Google Scholar 

  8. Kweon MH, Adhami VM, Lee JS, Mukhtar H (2006) Constitutive overexpression of Nrf2-dependent heme oxygenase-1 in A549 cells contributes to resistance to apoptosis induced by epigallocatechin 3-gallate. J Biol Chem 281:33761–33772. doi:10.1074/jbc.M604748200

    Article  CAS  PubMed  Google Scholar 

  9. Wang XJ, Sun Z, Villeneuve NF, Zhang S, Zhao F, Li Y, Chen W, Yi X, Zheng W, Wondrak GT, Wong PK, Zhang DD (2008) Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. Carcinogenesis 29:1235–1243. doi:10.1093/carcin/bgn095

    Article  CAS  PubMed  Google Scholar 

  10. Jin W, Wang H, Yan W, Xu L, Wang X, Zhao X, Yang X, Chen G, Ji Y (2008) Disruption of Nrf2 enhances upregulation of nuclear factor-kappaB activity, proinflammatory cytokines, and intercellular adhesion molecule-1 in the brain after traumatic brain injury. Mediators Inflamm 2008:725174. doi:10.1155/2008/725174

    Article  PubMed Central  PubMed  Google Scholar 

  11. Ma ZC, Hong Q, Wang YG, Tan HL, Xiao CR, Liang QD, Zhang BL, Gao Y (2010) Ferulic acid protects human umbilical vein endothelial cells from radiation induced oxidative stress by phosphatidylinositol 3-kinase and extracellular signal-regulated kinase pathways. Biol Pharm Bull 33:29–34. doi:10.1248/bpb.33.29

    Article  CAS  PubMed  Google Scholar 

  12. Lee S, Lim MJ, Kim MH, Yu CH, Yun YS, Ahn J, Song JY (2012) An effective strategy for increasing the radiosensitivity of Human lung Cancer cells by blocking Nrf2-dependent antioxidant responses. Free Radic Biol Med 53:807–816. doi:10.1016/j.freeradbiomed.2012.05.038

    Article  PubMed  Google Scholar 

  13. Das A, Banik NL, Patel SJ, Ray SK (2004) Dexamethasone protected human glioblastoma U87MG cells from temozolomide induced apoptosis by maintaining Bax:Bcl-2 ratio and preventing proteolytic activities. Mol Cancer 3:36. doi:10.1186/1476-4598-3-36

    Article  PubMed Central  PubMed  Google Scholar 

  14. Wang X, de Rivero Vaccari JP, Wang H, Diaz P, German R, Marcillo AE, Keane RW (2011) Activation of the nuclear factor E2-related factor 2/antioxidant response element pathway is neuroprotective after spinal cord injury. J Neurotrauma 29:936–945. doi:10.1089/neu 2011.1922

    Article  PubMed  Google Scholar 

  15. Wang JW, Wang HD, Zhong WZ, Li N, Cong ZX (2012) Expression and cell distribution of metabotropic glutamate receptor 5 in the rat cortex following traumatic brain injury. Brain Res 1464:73–81. doi:10.1016/j.brainres.2012.05.014

    Article  CAS  PubMed  Google Scholar 

  16. Pan H, Wang H, Zhu L, Mao L, Qiao L, Su X (2011) The Role of Nrf2 in Migration and Invasion of Human Glioma Cell U251. World Neurosurg. doi:10.1016/j.wneu.2011.06.063

    Google Scholar 

  17. Zhang DD (2010) The Nrf2-Keap1-ARE signaling pathway: the regulation and dual function of Nrf2 in cancer. Antioxid Redox Signal 13:1623–1626. doi:10.1089/ars 2010.3301

    Article  CAS  PubMed  Google Scholar 

  18. Zhou Y, Wang HD, Zhu L, Cong ZX, Li N, Ji XJ, Pan H, Wang JW, Li WC (2013) Knockdown of Nrf2 enhances autophagy induced by temozolomide in U251 human glioma cell line. Oncol Rep 29:394–400. doi:10.3892/or 2012.2115

    CAS  PubMed  Google Scholar 

  19. McDonald JT, Kim K, Norris AJ, Vlashi E, Phillips TM, Lagadec C, Della Donna L, Ratikan J, Szelag H, Hlatky L, McBride WH (2010) Ionizing radiation activates the Nrf2 antioxidant response. Cancer Res 70:8886–8895. doi:10.1158/0008-5472.can-10-0171

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Shim GS, Manandhar S, Shin DH, Kim TH, Kwak MK (2009) Acquisition of doxorubicin resistance in ovarian carcinoma cells accompanies activation of the NRF2 pathway. Free Radic Biol Med 47:1619–1631. doi:10.1016/j.freeradbiomed.2009.09.006

    Article  CAS  PubMed  Google Scholar 

  21. Wang XJ, Hayes JD, Wolf CR (2006) Generation of a stable antioxidant response element-driven reporter gene cell line and its use to show redox-dependent activation of Nrf2 by cancer chemotherapeutic agents. Cancer Res 66:10983–10994. doi:10.1158/0008-5472.CAN-06-2298

    Article  CAS  PubMed  Google Scholar 

  22. Pelicano H, Carney D, Huang P (2004) ROS stress in cancer cells and therapeutic implications. Drug Resist Updat 7:97–110. doi:10.1016/j.drup.2004.01.004

    Article  CAS  PubMed  Google Scholar 

  23. Trachootham D, Alexandre J, Huang P (2009) Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov 8:579–591. doi:10.1038/nrd2803

    Article  CAS  PubMed  Google Scholar 

  24. Wallace SS (1998) Enzymatic processing of radiation-induced free radical damage in DNA. Radiat Res 150:S60–S79

    Article  CAS  PubMed  Google Scholar 

  25. Kang KA, Lee IK, Zhang R, Piao MJ, Kim KC, Kim SY, Shin T, Kim BJ, Lee NH, Hyun JW (2010) Radioprotective effect of geraniin via the inhibition of apoptosis triggered by γ-radiation-induced oxidative stress. Cell Biol Toxicol 27:83–94. doi:10.1007/s10565-010-9172-4

    Article  PubMed  Google Scholar 

  26. Phillips TM, McBride WH, Pajonk F (2006) The Response of CD24-/low/CD44+breast cancer-initiating cells to radiation. J Natl Cancer Inst 98:1777–1785. doi:10.1093/jnci/djj495

    Article  PubMed  Google Scholar 

  27. Lin CJ, Lee CC, Shih YL, Lin TY, Wang SH, Lin YF, Shih CM (2012) Resveratrol enhances the therapeutic effect of temozolomide against malignant glioma in vitro and in vivo by inhibiting autophagy. Free Radic Biol Med 52:377–391. doi:10.1016/j.freeradbiomed.2011.10.487

    Article  CAS  PubMed  Google Scholar 

  28. Konstantinopoulos PA, Spentzos D, Fountzilas E, Francoeur N, Sanisetty S, Grammatikos AP, Hecht JL, Cannistra SA (2011) Keap1 mutations and Nrf2 pathway activation in epithelial ovarian. Cancer Res 71:5081–5089. doi:10.1158/0008-5472.CAN-10-4668

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by grants from the Key Subject of Jiangsu Province (X4200722), the Jinling Hospital of Nanjing (2012035) and the National Natural Science Foundation of China (81271377).

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Authors and Affiliations

  1. Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing, 210002, Jiangsu, China

    Zi-Xiang Cong, Han-Dong wang, Yuan Zhou, Jia-Wei Wang, Hao Pan, Ding-Ding Zhang, Li Zhang & Lin Zhu

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  1. Zi-Xiang Cong
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  2. Han-Dong wang
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  3. Yuan Zhou
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  7. Li Zhang
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Correspondence to Han-Dong wang.

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Cong, ZX., wang, HD., Zhou, Y. et al. Temozolomide and irradiation combined treatment-induced Nrf2 activation increases chemoradiation sensitivity in human glioblastoma cells. J Neurooncol 116, 41–48 (2014). https://doi.org/10.1007/s11060-013-1260-x

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  • DOI: https://doi.org/10.1007/s11060-013-1260-x

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