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Decreasing GSH and increasing ROS in chemosensitivity gliomas with IDH1 mutation

Tumor Biology volume 36, pages 655–662 (2015)Cite this article

Abstract

Gliomas are the most malignant and aggressive primary brain tumor in adults. Despite concerted efforts to improve therapies, their prognosis remains very poor. Isocitrate dehydrogenase 1 (IDH1) mutations have been discovered frequently in glioma patients and are strongly correlated with improved survival. However, the effect of IDH1 mutations on the chemosensitivity of gliomas remains unclear. In this study, we generated clonal U87 and U251 glioma cell lines overexpressing the R132H mutant protein (IDH1-R132H). Compared with control cells and cells overexpressing IDH wild type (IDH1-WT), both types of IDH1-R132H cells were more sensitive to temozolomide (TMZ) and cis-diamminedichloroplatinum (CDDP) in a time- and dose-dependent manner. The IDH1-R132H-induced higher chemosensitivity was associated with nicotine adenine disphosphonucleotide (NADPH), glutathione (GSH) depletion, and reactive oxygen species (ROS) generation. Accordingly, this IDH1-R132H-induced growth inhibition was effectively abrogated by GSH in vitro and in vivo. Our study provides direct evidence that the improved survival in patients with IDH1-R132H tumors may partly result from the effects of the IDH1-R132H protein on chemosensitivity. The primary cellular events associated with improved survival are the GSH depletion and increased ROS generation.

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References

  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009;59(4):225–49.

    Article  PubMed  Google Scholar 

  2. Su Y, Li G, Zhang X, Gu J, Zhang C, Tian Z, et al. JSI-124 inhibits glioblastoma multiforme cell proliferation through G(2)/M cell cycle arrest and apoptosis augment. Cancer Biol Ther. 2008;7(8):1243–9.

    CAS  Article  PubMed  Google Scholar 

  3. Yin D, Wakimoto N, Xing H, Lu D, Huynh T, Wang X, et al. Cucurbitacin B markedly inhibits growth and rapidly affects the cytoskeleton in glioblastoma multiforme. Int J Cancer. 2008;123(6):1364–75.

    CAS  Article  PubMed  Google Scholar 

  4. Jeon JY, An JH, Kim SU, Park HG, Lee MA. Migration of human neural stem cells toward an intracranial glioma. Exp Mol Med. 2008;40(1):84–91.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. Georgescu MM, Kirsch KH, Akagi T, Shishido T, Hanafusa H. The tumor-suppressor activity of PTEN is regulated by its carboxyl-terminal region. Proc Natl Acad Sci U S A. 1999;96(18):10182–7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321(5897):1807–12.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Sonoda Y, Kumabe T, Nakamura T, Saito R, Kanamori M, Yamashita Y, et al. Analysis of IDH1 and IDH2 mutations in Japanese glioma patients. Cancer Sci. 2009;100(10):1996–8.

    CAS  Article  PubMed  Google Scholar 

  8. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360(8):765–73.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Weller M, Felsberg J, Hartmann C, Berger H, Steinbach JP, Schramm J, et al. Molecular predictors of progression-free and overall survival in patients with newly diagnosed glioblastoma: a prospective translational study of the German Glioma Network. J Clin Oncol. 2009;27(34):5743–50.

    CAS  Article  PubMed  Google Scholar 

  10. Bleeker FE, Atai NA, Lamba S, Jonker A, Rijkeboer D, Bosch KS, et al. The prognostic IDH1 (R132) mutation is associated with reduced NADP+-dependent IDH activity in glioblastoma. Acta Neuropathol. 2010;119(4):487–94.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Dubbink HJ, Taal W, van Marion R, Kros JM, van Heuvel I, Bromberg JE, et al. IDH1 mutations in low-grade astrocytomas predict survival but not response to temozolomide. Neurology. 2009;73(21):1792–5.

    CAS  Article  PubMed  Google Scholar 

  12. Metellus P, Coulibaly B, Colin C, de Paula AM, Vasiljevic A, Taieb D, et al. Absence of IDH mutation identifies a novel radiologic and molecular subtype of WHO grade II gliomas with dismal prognosis. Acta Neuropathol. 2010;120(6):719–29.

    Article  PubMed  Google Scholar 

  13. Yan W, Zhang W, You G, Bao Z, Wang Y, Liu Y, et al. Correlation of IDH1 mutation with clinicopathologic factors and prognosis in primary glioblastoma: a report of 118 patients from China. PLoS One. 2012;7(1):e30339.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Xie F, Tang JJ, Wang X, Liu YH, Mao Q. Correlation between IDH1 mutation and prognosis in supratentorial high-grade astrocytomas. Sichuan Da Xue Xue Bao Yi Xue Ban. 2013;44(2):184–7. 192.

    CAS  PubMed  Google Scholar 

  15. Bujko M, Kober P, Matyja E, Nauman P, Dyttus-Cebulok K, Czeremszynska B. Prognostic value of IDH1 mutations identified with PCR-RFLP assay in glioblastoma patients. Mol Diagn Ther. 2010;14(3):163–9.

    CAS  Article  PubMed  Google Scholar 

  16. Hartmann C, Hentschel B, Tatagiba M, Schramm J, Schnell O, Seidel C, et al. Molecular markers in low-grade gliomas: predictive or prognostic? Clin Cancer Res. 2011;17(13):4588–99.

    CAS  Article  PubMed  Google Scholar 

  17. Houillier C, Wang X, Kaloshi G, Mokhtari K, Guillevin R, Laffaire J, et al. IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas. Neurology. 2010;75(17):1560–6.

    CAS  Article  PubMed  Google Scholar 

  18. van den Bent MJ, Dubbink HJ, Marie Y, Brandes AA, Taphoorn MJ, Wesseling P, et al. IDH1 and IDH2 mutations are prognostic but not predictive for outcome in anaplastic oligodendroglial tumors: a report of the European Organization for Research and Treatment of Cancer Brain Tumor Group. Clin Cancer Res. 2010;16(5):1597–604.

    Article  PubMed  Google Scholar 

  19. Sasaki M, Knobbe CB, Itsumi M, Elia AJ, Harris IS, Chio II, et al. d-2-Hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function. Genes Dev. 2012;26(18):2038–49.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. Mohrenz IV, Antonietti P, Pusch S, Capper D, Balss J, Voigt S, et al. Isocitrate dehydrogenase 1 mutant R132H sensitizes glioma cells to BCNU-induced oxidative stress and cell death. Apoptosis. 2013;18:1416–25.

    CAS  Article  PubMed  Google Scholar 

  21. Kim J, Kim JI, Jang HS, Park JW, Park KM. Protective role of cytosolic NADP(+)-dependent isocitrate dehydrogenase, IDH1, in ischemic pre-conditioned kidney in mice. Free Radic Res. 2011;45(7):759–66.

    CAS  Article  PubMed  Google Scholar 

  22. Geisbrecht BV, Gould SJ. The human PICD gene encodes a cytoplasmic and peroxisomal NADP(+)-dependent isocitrate dehydrogenase. J Biol Chem. 1999;274(43):30527–33.

    CAS  Article  PubMed  Google Scholar 

  23. Duran M, Kamerling JP, Bakker HD, van Gennip AH, Wadman SK. l-2-Hydroxyglutaric aciduria: an inborn error of metabolism? J Inherit Metab Dis. 1980;3(4):109–12.

    CAS  Article  PubMed  Google Scholar 

  24. Chuang JI, Chang TY, Liu HS. Glutathione depletion-induced apoptosis of Ha-ras-transformed NIH3T3 cells can be prevented by melatonin. Oncogene. 2003;22(9):1349–57.

    CAS  Article  PubMed  Google Scholar 

  25. Ghibelli L, Fanelli C, Rotilio G, Lafavia E, Coppola S, Colussi C, et al. Rescue of cells from apoptosis by inhibition of active GSH extrusion. FASEB J. 1998;12(6):479–86.

    CAS  PubMed  Google Scholar 

  26. Guha P, Dey A, Sen R, Chatterjee M, Chattopadhyay S, Bandyopadhyay SK. Intracellular GSH depletion triggered mitochondrial Bax translocation to accomplish resveratrol-induced apoptosis in the U937 cell line. J Pharmacol Exp Ther. 2011;336(1):206–14.

    CAS  Article  PubMed  Google Scholar 

  27. Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer. 2002;2(1):48–58.

    CAS  Article  PubMed  Google Scholar 

  28. Kretz-Remy C, Arrigo AP. Gene expression and thiol redox state. Methods Enzymol. 2002;348:200–15.

    CAS  Article  PubMed  Google Scholar 

  29. Juan ME, Wenzel U, Daniel H, Planas JM. Resveratrol induces apoptosis through ROS-dependent mitochondria pathway in HT-29 human colorectal carcinoma cells. J Agric Food Chem. 2008;56(12):4813–8.

    CAS  Article  PubMed  Google Scholar 

  30. Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009;361(11):1058–66.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. Guo C, Pirozzi CJ, Lopez GY, Yan H. Isocitrate dehydrogenase mutations in gliomas: mechanisms, biomarkers and therapeutic target. Curr Opin Neurol. 2011;24(6):648–52.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Lin CJ, Lee CC, Shih YL, Lin CH, Wang SH, Chen TH, et al. Inhibition of mitochondria- and endoplasmic reticulum stress-mediated autophagy augments temozolomide-induced apoptosis in glioma cells. PLoS One. 2012;7(6):e38706.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. Kohsaka S, Takahashi K, Wang L, Tanino M, Kimura T, Nishihara H, et al. Inhibition of GSH synthesis potentiates temozolomide-induced bystander effect in glioblastoma. Cancer Lett. 2013;331(1):68–75.

    CAS  Article  PubMed  Google Scholar 

  34. Oliva CR, Moellering DR, Gillespie GY, Griquer CE, et al. Acquisition of chemoresistance in gliomas is associated with increased mitochondrial coupling and decreased ROS production. PLoS One. 2011;6(9):e24665.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Schweyer S, Soruri A, Heintze A, Rzdzun HJ, Favvazi A. The role of reactive oxygen species in cisplatin-induced apoptosis in human malignant testicular germ cell lines. Int J Oncol. 2004;25(6):1671–6.

    CAS  PubMed  Google Scholar 

  36. Yu ZY, Liang YG, Xiao H, Shan YJ, Dong B, Huang R. Melissoidesin G, a diterpenoid purified from Isodon melissoides, induces leukemic-cell apoptosis through induction of redox imbalance and exhibits synergy with other anticancer agents. Int J Cancer. 2007;121(9):2084–94.

    CAS  Article  PubMed  Google Scholar 

  37. Das GC, Bacsi A, Shrivastav M, Hazra TK, Boldogh I. Enhanced gamma-glutamylcysteine synthetase activity decreases drug-induced oxidative stress levels and cytotoxicity. Mol Carcinog. 2006;45(9):635–47.

    CAS  Article  PubMed  Google Scholar 

  38. Li S, Chou AP, Chen W, Chen R, Deng Y, Phillips HS, et al. Overexpression of isocitrate dehydrogenase mutant proteins renders glioma cells more sensitive to radiation. Neuro Oncol. 2013;15(1):57–68.

    Article  PubMed  Google Scholar 

  39. Zhao S, Lin Y, Xu W, Jiang W, Zha Z, Wang P, et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science. 2009;324(5924):261–5.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462(7274):739–44.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. Szatrowski TP, Nathan CF. Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res. 1991;51(3):794–8.

    CAS  PubMed  Google Scholar 

  42. Hu Y, Rosen DG, Zhou Y, Feng L, Yang G, Liu J, et al. Mitochondrial manganese-superoxide dismutase expression in ovarian cancer: role in cell proliferation and response to oxidative stress. J Biol Chem. 2005;280(47):39485–92.

    CAS  Article  PubMed  Google Scholar 

  43. Toyokuni S. Oxidative stress and cancer: the role of redox regulation. Biotherapy. 1998;11(2–3):147–54.

    CAS  Article  PubMed  Google Scholar 

  44. Kondo S, Toyokuni S, Iwasa Y, Tanaka T, Onodera H, Hiai H, et al. Persistent oxidative stress in human colorectal carcinoma, but not in adenoma. Free Radic Biol Med. 1999;27(3–4):401–10.

    CAS  Article  PubMed  Google Scholar 

  45. Devi GS, Prasad MH, Saraswathi I, Raghu D, Rao DN, Reddy PP. Free radicals antioxidant enzymes and lipid peroxidation in different types of leukemias. Clin Chim Acta. 2000;293(1–2):53–62.

    CAS  Article  PubMed  Google Scholar 

  46. Hileman EA, Achanta G, Huang P. Superoxide dismutase: an emerging target for cancer therapeutics. Expert Opin Ther Targets. 2001;5(6):697–710.

    CAS  Article  PubMed  Google Scholar 

  47. Lyss G, Knorre A, Schmidt TJ, Pahl HL, Merfort I. The anti-inflammatory sesquiterpene lactone helenalin inhibits the transcription factor NF-kappaB by directly targeting p65. J Biol Chem. 1998;273(50):33508–16.

    CAS  Article  PubMed  Google Scholar 

  48. Ghantous A, Gali-Muhtasib H, Vuorela H, Saliba NA, Darwiche N. What made sesquiterpene lactones reach cancer clinical trials? Drug Discov Today. 2010;15(15–16):668–78.

    CAS  Article  PubMed  Google Scholar 

  49. Sharma V, Joseph C, Ghosh S, Agarwal A, Mishra MK, Sen E. Kaempferol induces apoptosis in glioblastoma cells through oxidative stress. Mol Cancer Ther. 2007;6(9):2544–53.

    CAS  Article  PubMed  Google Scholar 

  50. Pramanik KC, Boreddy SR, Srivastava SK. Role of mitochondrial electron transport chain complexes in capsaicin mediated oxidative stress leading to apoptosis in pancreatic cancer cells. PLoS One. 2011;6(5):e20151.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. Sun J, McKallip RJ. Plumbagin treatment leads to apoptosis in human K562 leukemia cells through increased ROS and elevated TRAIL receptor expression. Leuk Res. 2011;35(10):1402–8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. Franco R, Panayiotidis MI, Cidlowski JA. Glutathione depletion is necessary for apoptosis in lymphoid cells independent of reactive oxygen species formation. J Biol Chem. 2007;282(42):30452–65.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. Sun Y, St Clair DK, Xu Y, Crooks PA, St Clair WH. A NADPH oxidase-dependent redox signaling pathway mediates the selective radiosensitization effect of parthenolide in prostate cancer cells. Cancer Res. 2010;70(7):2880–90.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This study was supported by the Youth Fund of the National Natural Science Foundation of China (81201975; 81201979; 81201349), the Youth Fund of the Natural Science Foundation of Jiangsu Province (BK2012224), the Natural Science Foundation of China Ministry of Health (2010-2-025), the Natural Science Foundation of Jiangsu Department of Health (H201124), the Six Major Human Resources Project of Jiangsu Province (2011-WS-065; 2010-WS-038), and the Natural Science Foundation of Jiangsu Colleges and Universities Grant (11KJB320010).

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Affiliations

  1. Department of Neurosurgery, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, Jiangsu Province, 226001, China

    Jinlong Shi, Baolan Sun, Wei Shi, Hao Zuo, Lanchun Ni & Jian Chen

  2. Department of Neurosurgery, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200072, China

    Daming Cui

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  1. Jinlong Shi
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  2. Baolan Sun
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  3. Wei Shi
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  4. Hao Zuo
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  5. Daming Cui
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  6. Lanchun Ni
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  7. Jian Chen
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Corresponding authors

Correspondence to Lanchun Ni or Jian Chen.

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Animal experiments were performed in strict compliance with the institutional animal care guidelines.

Jinlong Shi and Baolan Sun contributed equally to the work.

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Fig. S1
figure 5

U251-IDH1-R132H cells increased the sensitivity to TMZ and CDDP. Cells were treated with varying doses of TMZ (A), CDDP (B), VCR (C), and VP-16 (D) for different incubation periods. Viability was quantitated with WST-1 assay and expressed as mean percentage of untreated control cells (mean ± SEM, n = 3). *P < 0.05, **P < 0.01 compared with control, IDH1-WT cells. (JPEG 43 kb)

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Shi, J., Sun, B., Shi, W. et al. Decreasing GSH and increasing ROS in chemosensitivity gliomas with IDH1 mutation. Tumor Biol. 36, 655–662 (2015). https://doi.org/10.1007/s13277-014-2644-z

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  • DOI: https://doi.org/10.1007/s13277-014-2644-z

Keywords

  • Gliomas
  • Isocitrate dehydrogenase 1
  • Glutathione
  • Reactive oxygen species
  • Chemotherapy