Skip to main content
SpringerLink
Log in

An IDH1 mutation inhibits growth of glioma cells via GSH depletion and ROS generation

  • Original Article
  • Published:
Neurological Sciences Aims and scope Submit manuscript

Abstract

The isocitrate dehydrogenase 1 (IDH1) gene mutation occurs frequently in glioma. While some studies have demonstrated that IDH1 mutations are associated with prolonged survival, the mechanism remains unclear. In this study, we found that growth was significantly inhibited in glioma cells overexpressing the mutated IDH1 gene. Furthermore, these cells were characterized by decreased intracellular NADPH levels accompanied by glutathione (GSH) depletion and reactive oxygen species (ROS) generation. Moreover, the increased apoptosis and the decreased proliferation were found in the glioma cells overexpressing the mutant IDH1 gene. Accordingly, our study demonstrates that using H2O2-regulated mutant IDH1 glioma cells could obviously increase the inhibition of cell growth; nevertheless, GSH had the opposite result. Our study provides direct evidence that mutation of IDH1 profoundly inhibits the growth of glioma cells, and we speculate that this is the major factor behind its association with prolonged survival in glioma. Finally, our study indicates that depletion of GSH and generation of ROS are the primary cellular events associated with this mutation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114(2):97–109

    Article  PubMed Central  PubMed  Google Scholar 

  2. Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359(5):492–507

    Article  CAS  PubMed  Google Scholar 

  3. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996

    Article  CAS  PubMed  Google Scholar 

  4. Ichimura K, Pearson DM, Kocialkowski S, Backlund LM, Chan R, Jones DT, Collins VP (2009) IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas. Neuro Oncol 11(4):341–347

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Sanson M, Marie Y, Paris S, Idbaih A, Laffaire J, Ducray F, El Hallani S, Boisselier B, Mokhtari K, Hoang-Xuan K, Delattre JY (2009) Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol 27(25):4150–4154

    Article  CAS  PubMed  Google Scholar 

  6. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360(8):765–773

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Kloosterhof NK, Bralten LB, Dubbink HJ, French PJ, van den Bent MJ (2011) Isocitrate dehydrogenase-1 mutations: a fundamentally new understanding of diffuse glioma? Lancet Oncol 12(1):83–91

    Article  CAS  PubMed  Google Scholar 

  8. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321(5897):1807–1812

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Menon SG, Goswami PC (2007) A redox cycle within the cell cycle: ring in the old with the new. Oncogene 26(8):1101–1109

    Article  CAS  PubMed  Google Scholar 

  10. Zhang Z, Leonard SS, Huang C, Vallyathan V, Castranova V, Shi X (2003) Role of reactive oxygen species and MAPKs in vanadate-induced G(2)/M phase arrest. Free Radic Biol Med 34(10):1333–1342

    Article  CAS  PubMed  Google Scholar 

  11. Sharma V, Joseph C, Ghosh S, Agarwal A, Mishra MK, Sen E (2007) Kaempferol induces apoptosis in glioblastoma cells through oxidative stress. Mol Cancer Ther 6(9):2544–2553

    Article  CAS  PubMed  Google Scholar 

  12. Deng S, Yang Y, Han Y, Li X, Wang X, Li X, Zhang Z, Wang Y (2012) UCP2 inhibits ROS-mediated apoptosis in A549 under hypoxic conditions. PLoS One 7(1):e30714

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Guha P, Dey A, Sen R, Chatterjee M, Chattopadhyay S, Bandyopadhyay SK (2011) Intracellular GSH depletion triggered mitochondrial Bax translocation to accomplish resveratrol-induced apoptosis in the U937 cell line. J Pharmacol Exp Ther 336(1):206–214

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  15. Izawa S, Maeda K, Miki T, Mano J, Inoue Y, Kimura A (1998) Importance of glucose-6-phosphate dehydrogenase in the adaptive response to hydrogen peroxide in Saccharomyces cerevisiae. Biochem J 330(Pt 2):811–817

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Rhee SG (1999) Redox signaling: hydrogen peroxide as intracellular messenger. Exp Mol Med 31(2):53–59

    Article  CAS  PubMed  Google Scholar 

  17. Shackelford RE, Kaufmann WK, Paules RS (1999) Cell cycle control, checkpoint mechanisms, and genotoxic stress. Environ Health Perspect 107(Suppl 1):5–24

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Bralten LB, Kloosterhof NK, Balvers R, Sacchetti A, Lapre L, Lamfers M, Leenstra S, de Jonge H, Kros JM, Jansen EE, Struys EA, Jakobs C, Salomons GS, Diks SH, Peppelenbosch M, Kremer A, Hoogenraad CC, Smitt PA, French PJ (2011) IDH1 R132H decreases proliferation of glioma cell lines in vitro and in vivo. Ann Neurol 69(3):455–463

    Article  CAS  PubMed  Google Scholar 

  19. Li S, Chou AP, Chen W, Chen R, Deng Y, Phillips HS, Selfridge J, Zurayk M, Lou JJ, Everson RG, Wu KC, Faull KF, Cloughesy T, Liau LM, Lai A (2013) Overexpression of isocitrate dehydrogenase mutant proteins renders glioma cells more sensitive to radiation. Neuro Oncol 15(1):57–68

    Article  PubMed Central  PubMed  Google Scholar 

  20. Chuang JI, Chang TY, Liu HS (2003) Glutathione depletion-induced apoptosis of Ha-ras-transformed NIH3T3 cells can be prevented by melatonin. Oncogene 22(9):1349–1357

    Article  CAS  PubMed  Google Scholar 

  21. Konishi T, Shimada Y, Nagao T, Okabe H, Konoshima T (2002) Antiproliferative sesquiterpene lactones from the roots of Inula helenium. Biol Pharm Bull 25(10):1370–1372

    Article  CAS  PubMed  Google Scholar 

  22. Lawrence NJ, McGown AT, Nduka J, Hadfield JA, Pritchard RG (2001) Cytotoxic Michael-type amine adducts of alpha-methylene lactones alantolactone and isoalantolactone. Bioorg Med Chem Lett 11(3):429–431

    Article  CAS  PubMed  Google Scholar 

  23. Ghantous A, Gali-Muhtasib H, Vuorela H, Saliba NA, Darwiche N (2010) What made sesquiterpene lactones reach cancer clinical trials? Drug Discov Today 15(15–16):668–678

    Article  CAS  PubMed  Google Scholar 

  24. Franco R, Panayiotidis MI, Cidlowski JA (2007) Glutathione depletion is necessary for apoptosis in lymphoid cells independent of reactive oxygen species formation. J Biol Chem 282(42):30452–30465

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Bleeker FE, Atai NA, Lamba S, Jonker A, Rijkeboer D, Bosch KS, Tigchelaar W, Troost D, Vandertop WP, Bardelli A, Van Noorden CJ (2010) The prognostic IDH1(R132) mutation is associated with reduced NADP+-dependent IDH activity in glioblastoma. Acta Neuropathol 119(4):487–494

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Koehler A, Van Noorden CJ (2003) Reduced nicotinamide adenine dinucleotide phosphate and the higher incidence of pollution-induced liver cancer in female flounder. Environ Toxicol Chem 22(11):2703–2710

    Article  CAS  PubMed  Google Scholar 

  27. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, Marks KM, Prins RM, Ward PS, Yen KE, Liau LM, Rabinowitz JD, Cantley LC, Thompson CB, Vander Heiden MG, Su SM (2010) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 465(7300):966

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the Youth Fund of the National Natural Science Foundation of China (81201975; 81201979), 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), the Natural Science Foundation of Jiangsu Colleges and Universities Grant (11KJB320010).

Conflict of interest

All the authors report no disclosures relevant to the manuscript. Animal experiments were performed in strict accordance with the Institutional Animal Care guidelines.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu, People’s Republic of China

    Jinlong Shi, Hao Zuo, Lanchun Ni, Liang Xia, Longxiang Zhao, Mingjie Gong, Dekang Nie, Peipei Gong, Wei Shi & Jian Chen

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

    Daming Cui

Authors
  1. Jinlong Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hao Zuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lanchun Ni
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Liang Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Longxiang Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mingjie Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dekang Nie
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Peipei Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Daming Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Wei Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jian Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jian Chen.

Additional information

J. Shi and H. Zuo contributed equally to the work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shi, J., Zuo, H., Ni, L. et al. An IDH1 mutation inhibits growth of glioma cells via GSH depletion and ROS generation. Neurol Sci 35, 839–845 (2014). https://doi.org/10.1007/s10072-013-1607-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10072-013-1607-2

Keywords

Search

Navigation